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Norepinephrine Dopamine |
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| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
|
NC or 25% increase
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
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|
| albuterol, | felodipine | norfloxacin |
| systemic and inhaled | finasteride | ofloxacin |
| amoxicillin | hydrocortisone | omeprazole |
| ampicillin, | isoflurane | prednisone, prednisolone |
| with or without sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
| famotidine | nizatidine | |
|
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See prescribing information for voriconazole. |
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The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
|
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|
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|
|
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
|
|
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. |
|
|
|
|
|
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted |
|
|
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. |
|
|
|
|
|
|
|
|
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. |
|
|
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy |
|
|
|
|
|
Increased exposure of citalopram leading to an increased risk of QT prolongation |
|
|
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. |
|
|
|
|
|
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) |
|
|
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. |
|
|
|
|
|
Potential for increased exposure of phenytoin. |
|
|
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. |
|
|
|
|
|
Increased exposure of diazepam |
|
|
Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
|
|
|
|
|
Potential for increased exposure of digoxin |
|
|
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. |
|
|
|
|
|
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
|
|
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF See the prescribing information for other drugs dependent on gastric pH for absorption. |
|
|
|
|
|
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. |
| Amoxicillin also has drug interactions. | |
|
|
See See |
|
|
|
|
|
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. |
|
|
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
|
|
|
|
|
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors |
|
|
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
|
|
|
|
|
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
|
|
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline |
|
|
|
|
|
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
|
|
An alternative confirmatory method should be considered to verify positive results. |
|
|
|
|
|
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
|
|
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole. |
|
|
|
|
|
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
|
|
|
|
|
|
|
|
|
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
|
|
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. |
|
|
|
|
|
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted
|
|
|
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. |
|
|
|
|
|
|
|
|
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. |
|
|
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy
|
|
|
|
|
|
Increased exposure of citalopram leading to an increased risk of QT prolongation
|
|
|
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. |
|
|
|
|
|
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol)
|
|
|
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. |
|
|
|
|
|
Potential for increased exposure of phenytoin. |
|
|
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. |
|
|
|
|
|
Increased exposure of diazepam
|
|
|
Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
|
|
|
|
|
Potential for increased exposure of digoxin
|
|
|
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. |
|
|
|
|
|
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
|
|
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF
See the prescribing information for other drugs dependent on gastric pH for absorption. |
|
|
|
|
|
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. |
| Amoxicillin also has drug interactions. | |
|
|
See
See |
|
|
|
|
|
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. |
|
|
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
|
|
|
|
|
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors
|
|
|
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
|
|
|
|
|
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
|
|
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline
|
|
|
|
|
|
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
|
|
An alternative confirmatory method should be considered to verify positive results. |
|
|
|
|
|
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
|
|
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole. |
|
|
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|
|
|
| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
|
NC or 25% increase
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
|
|
|
|
|
|
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| |
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| |
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| |
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| |
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| |
|
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| |
|
|
| |
Norepinephrine Dopamine |
|
| |
|
|
| |
|
|
| |
|
|
| Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours | Simultaneous dosing of Vardenafil and Alpha-Blocker | ||||
| Alpha-Blocker | Vardenafil 10 mg Placebo-Subtracted |
Vardenafil 20 mg Placebo-Subtracted |
Vardenafil 10 mg Placebo-Subtracted |
Vardenafil 20 mg Placebo-Subtracted |
|
| Terazosin 10 mg daily |
Standing SBP | -7 (-10, -3) | -11 (-14, -7) | -23 (-31, 16) |
-14 (-33, 11) |
| Supine SBP | -5 (-8, -2) | -7 (-11, -4) | -7 (-25, 19) |
-7 (-31, 22) |
|
| Tamsulosin 0.4 mg daily |
Standing SBP | -4 (-8, -1) | -8 (-11, -4) | -8 (-14, -2) | -8 (-14, -1) |
| Supine SBP | -4 (-8, 0) | -7 (-11, -3) | -5 (-9, -2) | -3 (-7, 0) | |
|
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|
Glucocorticoids Octreotide |
|
|
|
|
|
|
|
|
Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
|
|
|
|
|
Iodide (including iodine-containing radiographic contrast agents) |
|
|
|
|
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
|
|
|
|
|
|
|
|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
|
|
|
|
|
|
|
|
Hydantoins Phenobarbital Rifampin |
|
|
|
|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
|
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
|
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
|
|
|
|
|
- Interferon-α - Interleukin-2 |
|
|
- Somatrem - Somatropin |
|
|
|
|
|
- (e.g., Theophylline) |
|
|
|
|
|
|
|
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
|
|
|
Concentration of Lamotrigine or Concomitant Drug |
|
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
|
|
||
| Clinical Impact: | Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. | |
| Intervention: |
Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
|
|
|
|
||
| Clinical Impact: |
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
|
|
| Intervention: |
Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
|
|
|
|
||
| Clinical Impact: | NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. | |
| Intervention: |
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [
|
|
|
|
||
| Clinical Impact: |
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [
|
|
| Intervention: |
Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [
|
|
|
|
||
| Clinical Impact: | The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. | |
| Intervention: | During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. | |
|
|
||
| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. | |
| Intervention: | During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. | |
|
|
||
| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). | |
| Intervention: | During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. | |
|
|
||
| Clinical Impact: | Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity. | |
| Intervention: | During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. | |
|
|
||
| Clinical Impact: |
Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
|
|
| Intervention: | The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. | |
|
|
||
| Clinical Impact: | Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). | |
| Intervention: | During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. | |
|
|
||
| Clinical Impact: | When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. | |
| Intervention: | During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. | |
|
|
|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated. |
||
| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
|
|
|
| Tolbutamide; Sulfonylureas | Hypoglycemia potentiated |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result |
| Oral Anticoagulant | Increased bleeding |
| |
|
| Antacids, sucralfate, multivitamins, and other products containing multivalent cations | Moxifloxacin absorption is decreased. Administer moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin | Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
| Specific Drugs Reported | |||
| also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide |
diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine |
lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone |
propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton |
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| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
|
|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
|
|
|
|
|
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) inducers |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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| a Total estrogens is the sum of conjugated and unconjugated estrogen. | ||||||
|
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|||||
|
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|
|
|
|
|
|
| Estradiol | 0.037 ± 0.048 |
12.7 ± 9.1 |
0.676 ± 0.737 |
0.030 ± 0.032 |
17.32 ± 1.21 |
0.561 ± 0.572 |
| Estrone Total a |
3.68 ± 1.55 |
10.6 ± 6.8 |
61.3 ± 26.36 |
4.93 ± 2.07 |
7.5 ± 3.8 |
85.9 ± 41.2 |
| Equilin Total a |
2.27 ± 0.95 |
6.0 ± 4.0 |
28.8 ± 13.0 |
3.22 ± 1.13 |
5.3 ± 2.6 |
38.1 ± 20.2 |
|
|
|
|
| Atazanavir/Ritonavir | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. |
| Clarithromycin | ↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Efavirenz | ↓ Efavirenz | There has been no determination of appropriate doses for the safe and effective use of this combination [ |
| Ethinyl estradiol and Norethindrone | ↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Fluconazole | ↑Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Fosamprenavir | ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir | ↓ Amprenavir ↑ Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. |
| Indinavir | ↓ Indinavir | Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. |
| Ketoconazole | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Lopinavir/Ritonavir | ↓Lopinavir | Lopinavir/ritonavir 400/100 mg tablets can be used twice daily in combination with nevirapine with no dose adjustment in antiretroviral-naïve patients. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with nevirapine in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; and up to a maximum dose of 533/133 mg for those >45 kg twice daily when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected. |
| Methadone | ↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
| Nelfinavir | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. |
| Rifabutin | ↑Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
| Saquinavir/ritonavir | The interaction between VIRAMUNE and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
|
||
|
|
|
|
| Antiarrhythmics | Amiodarone, disopyramide, lidocaine | Plasma concentrations may be decreased. |
| Anticonvulsants | Carbamazepine, clonazepam, ethosuximide | Plasma concentrations may be decreased. |
| Antifungals | Itraconazole | Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. |
| Calcium channel blockers | Diltiazem, nifedipine, verapamil | Plasma concentrations may be decreased. |
| Cancer chemotherapy | Cyclophosphamide | Plasma concentrations may be decreased. |
| Ergot alkaloids | Ergotamine | Plasma concentrations may be decreased. |
| Immunosuppressants | Cyclosporin, tacrolimus, sirolimus | Plasma concentrations may be decreased. |
| Motility agents | Cisapride | Plasma concentrations may be decreased. |
| Opiate agonists | Fentanyl | Plasma concentrations may be decreased. |
| Antithrombotics | Warfarin | Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
|
|
| Anticoagulants
|
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
|
| Antiplatelet Agents
|
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
|
| Nonsteroidal Anti-Inflammatory Agents
|
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
|
| Serotonin Reuptake Inhibitors
|
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone
|
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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||
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|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| CYP2C9
|
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
|
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
|
| CYP1A2
|
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
|
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
|
| CYP3A4
|
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
|
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide
|
|
|
|
| Antacids, sucralfate, multivitamins, and other products containing multivalent cations | Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin | Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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|
| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
|
NC or 25% increase
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
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NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
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(Plasma Exposure Likely to be Increased and Prolonged) |
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Glucose-lowering effect potentiated |
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Altered serum levels of phenytoin (increased and decreased) |
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(transient elevations in serum creatinine) |
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(Increase in anticoagulant effect) |
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Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
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Two-fold increase in exposure |
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Five-fold increase in duloxetine exposure |
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Reduced clearance resulting in elevated levels and prolongation of serum half-life |
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| |
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| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| * Change relative to reference
|
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Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Recommendation |
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Inhibitors |
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daily |
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Do not exceed twice the patient’s usual dose |
|
Inhibitors |
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|
needed |
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needed |
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daily |
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|
needed |
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|
needed |
|
|
|
| Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin,
clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol |
Contraindicated with VYTORIN |
| Verapamil, diltiazem, dronedarone | Do not exceed 10/10 mg VYTORIN daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 10/20 mg VYTORIN daily |
| Lomitapide | For patients with HoFH, do not exceed 10/20 mg VYTORIN daily
|
| Grapefruit juice | Avoid grapefruit juice |
| Drug | Type of Interaction | Effect
|
|---|---|---|
| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases theophylline clearance doses ≥600 mg/day. | 25% increase at allopurinol |
| Amino glutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects. | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase.
Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline
|
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
|
|
|
|
|
|
||
| Estrogen-containing oral
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine
|
Decreased lamotrigine levels
approximately 50%. |
|
|
↓ levonorgestrel
|
Decrease in levonorgestrel component by 19%.
|
| Carbamazepine (CBZ) and
CBZ epoxide |
↓ lamotrigine
|
Addition of carbamazepine decreases lamotrigine
concentration approximately 40%. |
|
|
? CBZ epoxide
|
May increase CBZ epoxide levels
|
| Phenobarbital/Primidone
|
↓ lamotrigine
|
Decreased lamotrigine
concentration approximately 40%. |
| Phenytoin (PHT)
|
↓ lamotrigine
|
Decreased lamotrigine
concentration approximately 40% |
| Rifampin
|
↓ lamotrigine
|
Decreased lamotrigine AUC
approximately 40% |
| Valproate
|
↑ lamotrigine
|
Increased lamotrigine concentrations slightly
more than 2-fold. |
|
|
? valproate
|
Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
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|
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
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| |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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|
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
|
|
? carbamazepine epoxide |
May increase carbamazepine epoxide levels. |
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? valproate |
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
These drugs may increase serum thyroxine-binding globulin (TBG) concentration. |
| Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
These drugs may decrease serum TBG concentration. |
| Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations. | |
| Salicylates (> 2 g/day) | Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%. |
| Other drugs:
Carbamazepine Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates |
These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters. |
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There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. |
|
|
Closely monitor patients with concurrent use of buprenorphine and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine, and warn patients to use benzodiazepines concurrently with buprenorphine only as directed by their healthcare provider. |
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Due to additive pharmacologic effects, the concomitant use of non-benzodiazepine CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
|
|
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.2, 5.3)]. |
|
|
Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids. |
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The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine. |
|
|
If concomitant use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
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|
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
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The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression. |
|
|
If concomitant use is necessary, consider increasing the buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider buprenorphine dosage reduction and monitor for signs of respiratory depression. |
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Rifampin, carbamazepine, phenytoin |
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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. |
|
|
Patients who are on chronic buprenorphine treatment should have their dose monitored if NNRTIs are added to their treatment regimen. |
|
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efavirenz, nevirapine, etravirine, delavirdine |
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Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. |
|
|
Monitor patients taking buprenorphine and atazanavir with and without ritonavir, and reduce dose of buprenorphine if warranted. |
|
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atazanavir, ritonavir |
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Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. |
|
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None |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
|
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine if serotonin syndrome is suspected. |
|
|
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). |
|
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The use of buprenorphine is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
|
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phenelzine, tranylcypromine, linezolid |
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Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
|
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Monitor patients receiving muscle relaxants and buprenorphine for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine is used concomitantly with anticholinergic drugs. |
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See prescribing information for voriconazole. |
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(Mechanism of |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(400 mg every 12h)** (CYP450 Induction) Low-dose Ritonavir (100 mg every 12h)** (CYP450 Induction) |
Reduced |
Coadministration of voriconazole and low-dose ritonavir (100 mg every 12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
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(CYP450 Induction) |
to Result in Significant Reduction |
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(CYP450 Induction) |
to Result in Significant Reduction |
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(CYP450 Induction) |
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(CYP450 inducer; P-gp inducer) |
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containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
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(CYP2C9, CYP2C19 and CYP3A4 Inhibition) |
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Inhibitors (CYP3A4 Inhibition) |
In Vitro |
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
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(CYP3A4 Inhibition or CYP450 Induction) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Careful assessment of voriconazole effectiveness |
| Everolimus (CYP3A4 Inhibition) |
Not Studied |
Concomitant administration of voriconazole and everolimus is not recommended. |
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| *Results based on **Results based on ***Results based on ****Non-Steroidal Anti-Inflammatory Drug *****Non-Nucleoside Reverse Transcriptase Inhibitors |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(400 mg q12h)** (CYP3A4 Inhibition) |
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(100 mg q12h)** |
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(CYP450 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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including ibuprofen and diclofenac |
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(CYP3A4 Inhibition)** |
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(CYP3A4 Inhibition) |
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(CYP2C9 Inhibition) |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. |
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| Allopurinol |
|
25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. |
|
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increase theophylline clearance. | 20% increase |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20 to 40% decrease |
| Sulfinpyrazone | Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% increase |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33 to 100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
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of monoamine oxidase inhibitors (MAOI). |
May cause acute hypertensive crisis. |
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antidepressants. |
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sympathomimetic agents and with epinephrine or other sympathomimetics. |
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of propranolol or other β-adrenergic blockers. |
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response enhanced. |
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of phentolamine or other α-adrenergic blockers. |
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as amphetamines or phenylpropanolamine. |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
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| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – Antagonist: maraviroc |
↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
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| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers: dihydropyridine, felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Long-acting beta-adrenoceptor Agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
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Concentration Increase |
Increase |
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Drug |
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(Risperidone + 9- Hydroxy-Risperidone (Ratio |
Recommendation |
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(CYP 2D6) Inhibitors |
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twice daily |
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dosing. Do not exceed 8 mg/day |
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dosing. Do not exceed 8 mg/day |
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(CYP3A/PgP inducers) |
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mg/day |
daily |
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upwards. Do not exceed twice the patient’s usual dose |
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(CYP3A) Inhibitors |
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daily |
dose |
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not needed |
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daily |
dose |
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not needed |
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daily |
dose |
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not needed |
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daily |
daily |
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not needed |
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| Interacting Agents | Prescribing Recommendations |
|---|---|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
| ↓= Decreased (induces lamotrigine glucuronidation). | ||
| ↑= Increased (inhibits lamotrigine glucuronidation). | ||
| ? = Conflicting data. | ||
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contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
concentrations approximately 50%. |
|
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component by 19%. |
|
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Carbamazepine epoxide |
|
lamotrigine concentration approximately 40%. |
|
epoxide. |
Epoxide levels. |
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approximately 50%. |
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approximately 32%. |
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approximately 40%. |
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approximately 40%. |
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approximately 40%. |
|
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slightly more than 2-fold. |
|
|
regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
|
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| |
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
|
|
|
| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level (
|
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (
|
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (
|
| Phenytoin | Monitor phenytoin level (
|
| Methotrexate | Monitor for methotrexate toxicity (
|
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine (
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets (
|
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant uses of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
|
Monitor patients with concomitant use of indomethacin capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
|
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Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
|
|
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin capsules and triamterene should not be administered together. Both Indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. |
|
|
Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [ |
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The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
|
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During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
|
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During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
|
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During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. |
|
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During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
|
|
The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. |
|
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Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
|
|
During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. |
|
|
During the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. |
| Drugs that Affect Renal Function |
A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin. |
|
| Antiarrthymics | Dofetilide | Concomitant administration with digoxin was associated with a higher rate of torsades de pointes |
| Sotalol | Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. | |
| Dronedarone | Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin. | |
| Parathyroid Hormone Analog | Teriparatide | Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. |
| Thyroid supplement | Thyroid | Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. |
| Sympathomimetics | Epinephrine Norepinephrine Dopamine |
Can increase the risk of cardiac arrhythmias |
| Neuromuscular Blocking Agents | Succinylcholine | May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin. |
| Supplements | Calcium | If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. |
| Beta-adrenergic blockers and calcium channel blockers | Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block. | |
| Hyperpolarization-activated cyclic nucleotide-gated channel blocker | Ivabradine | Can increase the risk of bradycardia. |
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The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
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Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
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|
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. |
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Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted |
|
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A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. |
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Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. |
|
|
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy |
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Increased exposure of citalopram leading to an increased risk of QT prolongation |
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Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. |
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Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) |
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Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. |
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Potential for increased exposure of phenytoin. |
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Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. |
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Increased exposure of diazepam |
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Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
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Potential for increased exposure of digoxin |
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Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. |
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Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
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Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF See the prescribing information for other drugs dependent on gastric pH for absorption. |
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Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. |
| Amoxicillin also has drug interactions. | |
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See See |
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Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. |
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Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
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Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors |
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Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
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Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
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Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline |
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There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
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An alternative confirmatory method should be considered to verify positive results. |
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There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
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Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole. |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Strong CYP3A4 inhibitors (e.g.,itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicstat-containing products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily* |
| Grapefruit juice |
Avoid grapefruit juice |
| 1A2 | 2C9 | 3A4 | 2C19 |
|---|---|---|---|
| Warfarin | Warfarin | Alprazolam | Omeprazole |
| Theophylline | |||
| Propranolol | |||
| Tizanidine |
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The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome. |
|
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Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue |
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selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
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Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias. |
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Concomitant use of pimozide and sertraline hydrochloride is contraindicated |
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The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome. |
|
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Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs |
|
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other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort |
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The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding. |
|
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Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio |
|
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aspirin, clopidogrel, heparin, warfarin |
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Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma |
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Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted. |
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warfarin |
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Sertraline hydrochloride is a CYP2D6 inhibitor |
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Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued. |
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propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine |
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Phenytoin is a narrow therapeutic index drug. sertraline hydrochloride may increase phenytoin concentrations. |
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Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed. |
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phenytoin, fosphenytoin |
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| Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements. | |
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| Phenobarbital Rifampin |
Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine. |
| |
|
|
| Rifampin* and Rifabutin*
(CYP450 Induction) |
Significantly Reduced | |
| Efavirenz (400 mg q24h)**
(CYP450 Induction) |
Significantly Reduced | |
| Efavirenz (300 mg q24h)**
(CYP450 Induction) |
Slight Decrease in AUCτ | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h)**
(CYP450 Induction) |
Significantly Reduced | |
| Low-dose Ritonavir (100 mg q12h)**
(CYP450 Induction) |
Reduced | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied but Likely to Result in Significant Reduction |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied but Likely to Result in Significant Reduction |
|
| Phenytoin*
(CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John’s Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced | |
| Oral Contraceptives**
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) |
Significantly Increased | Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
Significant Effects of Indinavir on Voriconazole Exposure |
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir |
| Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
|
| Other NNRTIs***
(CYP3A4 Inhibition or CYP450 Induction) |
Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to voriconazole |
| A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Careful assessment of voriconazole effectiveness |
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atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
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fibrates, gemfibrozil |
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digoxin |
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|---|---|---|
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
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| Grapefruit juice | Avoid grapefruit juice |
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| Drugs | Effect on Concentration | Clinical Comment |
|---|---|---|
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zidovudine |
↔ zidovudine | Monitor blood cell count and suppressive effect on bone marrow function when zidovudine is coadministered with PegIntron. |
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e.g., cyclosporine sirolimus tacrolimus |
Effect on immunosuppressants unknown | Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with PegIntron. |
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methadone |
↑ methadone | Methadone dosage may need to be reduced when coadministered with PegIntron. |
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thioridazine |
↑ thioridazine | Monitor for thioridazine adverse events when coadministered with PegIntron. |
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theophylline |
↑ theophylline | Monitor for theophylline adverse events when coadministered with PegIntron. |
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carbamazepine, phenytoin, rifampin) |
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| Drug | Type of Interaction | Effect |
|---|---|---|
| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases theophylline clearance doses ≥600 mg/day. | 25% increase at allopurinol |
| Amino glutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% decrease |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Large diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects. | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline | 20% decrease |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifyline (PB) | Similar to aminogluethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance to theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
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• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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(Mechanism of Interaction by Voriconazole) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP450 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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| Drug | Type of Interaction | Effect** |
|
Adenosine |
Theophylline blocks adenosine receptors. |
Higher doses of adenosine may be required to achieve desired effect. |
|
Alcohol |
A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. |
30% increase |
|
Allopurinol |
Decreases theophylline clearance at allopurinol doses ≥600 mg/day. |
25% increase |
|
Aminoglutethimide |
Increases theophylline clearance by induction of microsomal enzyme activity. |
25% decrease |
|
Carbamazepine |
Similar to aminoglutethimide. |
30% decrease |
|
Cimetidine |
Decreases theophylline clearance by inhibiting cytochrome P450 1A2. |
70% increase |
|
Ciprofloxacin |
Similar to cimetidine. |
40% increase |
|
Clarithromycin |
Similar to erythromycin. |
25% increase |
|
Diazepam |
Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. |
Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
|
Disulfiram |
Decreases theophylline clearance by inhibiting hydroxylation and demethylation. |
50% increase |
|
Enoxacin |
Similar to cimetidine. |
300% increase |
|
Ephedrine |
Synergistic CNS effects. |
Increased frequency of nausea, nervousness, and insomnia. |
|
Erythromycin |
Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. |
35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
|
Estrogen |
Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. |
30% increase |
|
Flurazepam |
Similar to diazepam. |
Similar to diazepam. |
|
Fluvoxamine |
Similar to cimetidine. |
Similar to cimetidine. |
|
Halothane |
Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. |
Increased risk of ventricular arrhythmias. |
|
Interferon, human recombinant alpha-A |
Decreases theophylline clearance. |
100% increase |
|
Isoproterenol (IV) |
Increases theophylline clearance. |
20% decrease |
|
Ketamine |
Pharmacologic. |
May lower theophylline seizure threshold |
|
Lithium |
Theophylline increases renal lithium clearance. |
Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
|
Lorazepam |
Similar to diazepam. |
Similar to diazepam. |
|
Methotrexate (MTX) |
Decreases theophylline clearance. |
20% increase after low dose MTX, higher dose MTX may have a greater effect. |
|
Mexiletine |
Similar to disulfiram. |
80% increase |
|
Midazolam |
Similar to diazepam. |
Similar to diazepam. |
|
Moricizine |
Increases theophylline clearance. |
25% decrease |
|
Pancuronium |
Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. |
Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
|
Pentoxifylline |
Decreases theophylline clearance. |
30% increase |
|
Phenobarbital (PB) |
Similar to aminoglutethimide. |
25% decrease after two weeks of concurrent PB. |
|
Phenytoin |
Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. |
Serum theophylline |
|
Propafenone |
Decreases theophylline clearance and pharmacologic interaction. |
40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
|
Propranolol |
Similar to cimetidine and pharmacologic interaction. |
100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
|
Rifampin |
Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. |
20-40% decrease |
| St. John’sWort (Hypericum Perforatum) | Decrease in theophylline plasma concentrations. | Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity. |
|
Sulfinpyrazone |
Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. |
20% decrease |
|
Tacrine |
Similar to cimetidine, also increases renal clearance of theophylline. |
90% increase |
|
Thiabendazole |
Decreases theophylline clearance. |
190% increase |
|
Ticlopidine |
Decreases theophylline clearance. |
60% increase |
|
Troleandomycin |
Similar to erythromycin. |
33-100% increase depending on troleandomycin dose. |
|
Verapamil |
Similar to disulfiram. |
20% increase |
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) | Do not exceed 40 mg atorvastatin daily |
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| Estrogen-containing oral contraceptivepreparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
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and carbamazepine epoxide |
? carbamazepine epoxide |
May increase carbamazepine epoxide levels. |
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| Valproate | ↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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| Dopamine/Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone
Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. | ||
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| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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Gemfibrozil significantly increased repaglinide exposures by 8.1 fold |
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Do not administer repaglinide to patients receiving gemfibrozil |
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Clopidogrel increased repaglinide exposures by 3.9 to 5.1 fold |
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Avoid concomitant use of repaglinide with clopidogrel. If concomitant use can not be avoided, initiate repaglinide at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg |
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Cyclosporine increased low dose repaglinide exposures by 2.5 fold |
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Daily maximum repaglinide dose should be limited to 6 mg, and increased frequency of glucose monitoring may be required when repaglinide is co-administered with cyclosporine. |
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Repaglinide dose reductions and increased frequency of glucose monitoring may be required when co-administered. |
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Drugs that are known to inhibit CYP3A4 include antifungal agents (ketoconazole, itraconazole) and antibacterial agents (clarithromycin, erythromycin). Drugs that are known to inhibit CYP2C8 include trimethoprim, gemfibrozil, montelukast, deferasirox, and clopidiogrel. |
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Repaglinide dose increases and increased frequency of glucose monitoring may be required when co-administered. |
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Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine |
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Repaglinide dose reductions and increased frequency of glucose monitoring may be required when co-administered. |
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Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory agents (NSAIDs), pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics |
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Repaglinide dose increases and increased frequency of glucose monitoring may be required when co-administered. |
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Atypical antipsychotics (e.g., olanzapine and clozapine), calcium channel antagonists, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. |
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Increased frequency of glucose monitoring may be required when repaglinide is co-administered with these drugs. |
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beta-blockers, clonidine, guanethidine, and reserpine |
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| Theophylline |
Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents |
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin |
Monitor phenytoin level ( |
| Methotrexate |
Monitor for methotrexate toxicity ( |
| Cyclosporine |
May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( |
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| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Factors | Dosage Adjustments for Aripiprazole |
| Known CYP2D6 Poor Metabolizers | Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP2D6 or CYP3A4 inhibitors | Administer half of usual dose |
| Strong CYP2D6 and CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
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|||||
| Coadministered Drug | Dose of Coadministered Drug | Dose of Azithromycin | n | Ratio (with/without coadministered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00 | |
| Mean Cmax | Mean AUC | ||||
| Efavirenz | 400 mg/day x 7 days | 600 mg PO on day 7 | 14 | 1.22 (1.04 to 1.42) | 0.92* |
| Fluconazole | 200 mg PO single dose | 1,200 mg PO single dose | 18 | 0.82 (0.66 to 1.02) | 1.07 (0.94 to 1.22) |
| Nelfinavir | 750 mg TID x 11 days | 1,200 mg PO on day 9 | 14 | 2.36 (1.77 to 3.15) | 2.12 (1.80 to 2.50) |
| Rifabutin | 300 mg/day x 10 days | 500 mg PO on day 1, then 250 mg/day on days 2 to 10 | 6 | See footnote below | NA |
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The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
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Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue
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selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
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Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
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Concomitant use of pimozide and sertraline hydrochloride is contraindicated
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The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
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Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs
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other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
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The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
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Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio
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aspirin, clopidogrel, heparin, warfarin
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Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma
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Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
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warfarin
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Sertraline hydrochloride is a CYP2D6 inhibitor
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Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
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propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
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Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
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Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
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phenytoin, fosphenytoin
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| Drug or Drug Class | Effect |
|---|---|
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| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
|
** Results based on ** Results based on *** Non-Nucleoside Reverse Transcriptase Inhibitors |
||
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|
|
| Rifampin* and Rifabutin*
(CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (400 mg q24h)**
(CYP450 Induction) Efavirenz (300 mg q24h)** (CYP450 Induction) |
Significantly Reduced Slight Decrease in |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h)** (CYP450 Induction) Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction) |
Significantly Reduced Reduced |
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin*
(CYP450 Induction) |
Significantly Reduced |
Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John’s Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased |
Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) |
Significantly Increased |
Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
| Other NNRTIs***
(CYP3A4 Inhibition or CYP450 Induction) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness |
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The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression |
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If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation. |
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Quinidine, fluoxetine, paroxetine and bupropion |
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The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) |
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The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase |
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If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended. |
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Rifampin, carbamazepine, phenytoin |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome |
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Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets is used concomitantly with anticholinergic drugs. |
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Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity. |
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Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed. |
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Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times. |
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Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed. |
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atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
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fibrates, gemfibrozil |
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digoxin |
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| CYP2C9
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amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
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aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
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| CYP1A2
|
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
|
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
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| CYP3A4
|
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
|
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide
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|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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Monitor patients with concomitant use of naproxen with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone |
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|
Concomitant use of naproxen and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding Naproxen are not substitutes for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of naproxen with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects |
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The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin |
|
|
During concomitant use of naproxen and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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|
During concomitant use of naproxen and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of naproxen and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of naproxen and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of naproxen and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy |
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|
The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. |
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Concomitant use of naproxen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
|
|
During concomitant use of naproxen and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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|
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Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. |
|
|
Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen is not recommended. |
|
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|
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Concomitant administration of cholestyramine can delay the absorption of naproxen. |
|
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Concomitant administration of cholestyramine with naproxen is not recommended. |
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Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. |
|
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Patients simultaneously receiving naproxen and probenecid should be observed for adjustment of dose if required. |
|
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|
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Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. |
|
|
Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. |
|
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| Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide |
Not Recommended |
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
| Digoxin | Use With Caution |
|
| Oral Anticoagulants: Warfarin |
Use With Caution |
|
| Antiepileptics: Carbamazepine |
Use With Caution |
|
| Antifungals: Itraconazole |
|
|
| Fluconazole | No Dose Adjustment |
|
| Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal or hepatic function) |
Contraindicated Use With Caution |
|
| Antipsychotics: Pimozide Quetiapine |
Contraindicated | |
| Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity) |
Use With Caution |
|
| Antivirals: Atazanavir |
Use With Caution |
|
| Saquinavir (in patients with decreased renal function) |
|
|
| Ritonavir Etravirine |
|
|
| Maraviroc |
|
|
| Boceprevir (in patients with normal renal function) Didanosine |
No Dose Adjustment |
|
| Zidovudine |
The impact of co-administration of clarithromycin extended-release tablets and zidovudine has not been evaluated. |
|
| Calcium Channel Blockers: Verapamil | Use With Caution |
|
| Amlodipine Diltiazem |
|
|
| Nifedipine |
|
|
| Ergot Alkaloids: Ergotamine Dihydroergotamine |
Contraindicated |
|
| Gastroprokinetic Agents: Cisapride |
Contraindicated | |
| HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin |
Contraindicated | |
| Atorvastatin Pravastatin |
Use With Caution | |
| Fluvastatin | No Dose Adjustment | |
| Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone |
Use With Caution |
|
| Insulin |
|
|
| Immunosuppressants: Cyclosporine |
Use With Caution |
|
| Tacrolimus |
|
|
| Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil |
Use With Caution |
|
| Proton Pump Inhibitors: Omeprazole |
No Dose Adjustment |
|
| Xanthine Derivatives: Theophylline |
Use With Caution |
|
| Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam |
Use With Caution |
|
| Alprazolam Triazolam |
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
|
| Temazepam Nitrazepam Lorazepam |
No Dose Adjustment |
|
| Cytochrome P450 Inducers: Rifabutin |
Use With Caution |
|
| Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution | There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. |
| Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate |
Use With Caution | There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. |
|
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||
|
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|
| Antifungals: Itraconazole |
Use With Caution |
|
| Antivirals: Atazanavir |
Use With Caution |
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co- administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to |
| Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) |
Doses of clarithromycin greater than 1,000 mg per day should not be co-administered with protease inhibitors. |
|
| Etravirine |
|
|
| Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function) |
No Dose Adjustment | |
| Proton Pump Inhibitors: Omeprazole |
Use With Caution |
|
| Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine |
Use With Caution | Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under "Drugs That Are Affected By clarithromycin" in the table above). |
| Drug Class | Contraindicated | Not Recommended | Use with Caution | Comments |
|---|---|---|---|---|
|
|
|
|
||
| Alpha Blockers | tamsulosin | |||
| Analgesics | methadone | alfentanil,
buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil |
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| Antiarrhythmics | disopyramide,
dofetilide, dronedarone, quinidine |
digoxin |
|
|
| Antibacterials | telithromycin, in subjects with severe renal impairment or severe hepatic impairment | rifabutin | telithromycin |
|
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||||
| Anticoagulants and Antiplatelet Drugs | ticagrelor | apixaban,
rivaroxaban |
coumarins,
cilostazol, dabigatran |
|
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||||
| Anticonvulsants | carbamazepine |
|
||
| Antidiabetics | repaglinide,
saxagliptin |
|||
| Antihelmintics and Antiprotozoals | praziquantel | |||
| Antimigraine Drugs | ergot alkaloids, such as dihydroergotamine,
ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine) |
eletriptan |
|
|
| Antineoplastics | irinotecan | axitinib,
dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib, trabectedin |
bortezomib,
busulphan, docetaxel, erlotinib, gefitinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids |
|
| Antipsychotics, Anxiolytics and Hypnotics | lurasidone,
oral midazolam, pimozide, triazolam |
alprazolam,
aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone |
|
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|
||||
| Antivirals | simeprevir | maraviroc,
indinavir, ritonavir, saquinavir |
|
|
| Beta Blockers | nadolol | |||
| Calcium Channel Blockers | felodipine,
nisoldipine |
other dihydropyridines,
verapamil |
|
|
| Cardiovascular Drugs, Miscellaneous | Ivabradine,
ranolazine |
aliskiren,
sildenafil, for the treatment of pulmonary hypertension |
bosentan,
riociguat |
|
| Diuretics | eplerenone |
|
||
| Gastrointestinal Drugs | cisapride | aprepitant |
|
|
| Immunosuppressants | everolimus,
temsirolimus |
budesonide,
ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus |
||
| Lipid Regulating Drugs | lovastatin,
simvastatin |
atorvastatin | The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. | |
| Respiratory Drugs | salmeterol | |||
| Urological Drugs | fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment,
solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment |
darifenacin,
vardenafil |
fesoterodine.
oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine |
|
| Other | colchicine, in subjects with renal or hepatic impairment | colchicine,
conivaptan, tolvaptan |
cinacalcet |
|
|
|
|
|
|
|
e.g., |
5 days |
|
e.g., tri-iodothyronine |
2 weeks |
|
expectorants, vitamins |
2 weeks |
|
|
|
|
|
Up to 1 year |
|
corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium |
1 week 1 week 1 week 1-2 weeks 4 weeks |
|
|
|
| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Classes of Drugs | |||
| 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials |
Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors† |
Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins† |
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| *Change relative to reference |
|||||
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(Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Recommendation |
||
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|
Re-evaluate dosing. Do not exceed 8 mg/day |
|
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Re-evaluate dosing. Do not exceed 8 mg/day |
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Titrate dose upwards. Do not exceed twice the patient’s usual dose |
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| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (
|
|
|
|
|
|
|
Avoid atorvastatin
|
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily
|
| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
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||
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|
|||
| Dopamine/Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
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|
|||
| Aminoglutethimide
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone
Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
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|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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||
| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. | ||
|
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|||
|
|
|||
| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
(mg/day) |
Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400 to 2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 >1200 to 2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
|
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Monitor patients with concomitant use of VOLTAREN
® GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding
|
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone
|
||
|
|
Concomitant use of VOLTAREN
® GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding
|
||
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|||
|
|
• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme
|
||
|
|
• During concomitant use of VOLTAREN
® GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
|
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|
|
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. | ||
|
|
During concomitant use of VOLTAREN
® GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects
|
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The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. | ||
|
|
During concomitant use of VOLTAREN ® GEL and digoxin, monitor serum digoxin levels. | ||
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|
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. | ||
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During concomitant use of VOLTAREN ® GEL and lithium, monitor patients for signs of lithium toxicity. | ||
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). | ||
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During concomitant use of VOLTAREN ® GEL and methotrexate, monitor patients for methotrexate toxicity. | ||
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Concomitant use of VOLTAREN ® GEL and cyclosporine may increase cyclosporine's nephrotoxicity. | ||
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During concomitant use of VOLTAREN ® GEL and cyclosporine, monitor patients for signs of worsening renal function. | ||
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Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy
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The concomitant use of diclofenac with other NSAIDs or salicylates is notrecommended. | ||
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Concomitant use of VOLTAREN ® GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). | ||
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During concomitant use of VOLTAREN
® GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity.
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Amprenavir |
1200 mg BID x 10 days |
300 mg QD x 10 days |
Healthy male subjects (6) |
↑ AUC by 193%, ↑ Cm
a
x by 119% |
↔ |
Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions. |
| Delavirdine |
400 mg TID |
300 mg QD |
HIV-infected patients (7) |
↑ AUC by 230%, ↑ Cm
a
x by 128% |
↓ AUC by 80%, ↓ Cmax by 75%, ↓ Cm i n by 17% |
|
| Didanosine |
167 or 250 mg BID x 12 days |
300 or 600 mg QD x 1 |
HIV-infected patients (11) |
↔ |
↔ |
|
| Fosamprenavir/ ritonavir |
700 mg BID plus ritonavir 100 mg BID x 2 weeks |
150 mg every other day x 2 weeks |
Healthy subjects (15) |
↔ AUCa
↓ Cm
a
x by 15% |
↑ AUC by 35%b, ↑ Cm a x by 36%, ↑ Cm i n by 36% |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination. |
| Indinavir |
800 mg TID x 10 days |
300 mg QD x 10 days |
Healthy subjects (10) |
↑ AUC by 173%, ↑ Cmax by 134% |
↓ AUC by 34%, ↓ Cm
a
x by 25%, ↓ Cm
i
n by 39% |
Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID. |
| Lopinavir/ ritonavir |
400/100 mg BID x 20 days |
150 mg QD x 10 days |
Healthy subjects (14) |
↑ AUC by 203%c
↓ Cm a x by 112% |
↔ |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Saquinavir/ ritonavir |
1000/100 mg BID x 14 or 22 days |
150 mg every 3 days X 21 to 22 days |
Healthy subjects |
↑ AUC by 53% d ↑ Cm
a
x by 88% (n=11) |
↓ AUC by 13%, ↓ Cm
a
x by 15%, (n=19) |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions. |
| Ritonavir |
500 mg BID x 10 days |
150 mg QD x 16 days |
Healthy subjects (5) |
↑ AUC by 300%, ↑ Cm
a
x by 150% |
ND |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Tipranavir/ ritonavir |
500/200 BID X 15 doses |
150 mg single dose |
Healthy subjects (20) |
↑ AUC by 190%, ↑ Cm
a
x by 70% |
↔ |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Nelfinavir |
1250 mg BID x 7 to 8 days |
150 mg QD x 8 days |
HIV-infected patients (11) |
↑ AUC by 83%,e ↑ Cm
a
x by 19% |
↔ |
Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID |
| Zidovudine |
100 or 200 mg q4h |
300 or 450 mg QD |
HIV-infected patients (16) |
↔ |
↓ AUC by 32%, ↓ Cm
a
x by 48% |
Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary. |
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| Fluconazole |
200 mg QD x 2 weeks |
300 mg QD x 2 weeks |
HIV-infected patients (12) |
↑ AUC by 82%, ↑ Cm
a
x by 88% |
↔ |
Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected. |
| Posaconazole |
200 mg QD x 10 days |
300 mg QD x 17 days |
Healthy subjects (8) |
↑ AUC by 72%, ↑ Cm
a
x by 31% |
↓ AUC by 49%, ↓ Cm
a
x by 43% |
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy. |
| Itraconazole |
200 mg QD |
300 mg QD |
HIV-Infected patients (6) |
↑f
|
↓ AUC by 70%, ↓ Cm
a
x by 75% |
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following coadministration of rifabutin (300 mg QD) with itraconazole (600 to 900 mg QD). |
| Voriconazole |
400 mg BID x 7 days (maintenance dose) |
300 mg QD x 7 days |
Healthy male subjects (12) |
↑ AUC by 331%, ↑ Cm
a
x by 195% |
↑ AUC by ~100%, ↑ Cm a x by ~100%g |
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| Dapsone |
50 mg QD |
300 mg QD |
HIV-infected patients (16) |
ND |
↓ AUC by 27 to 40% |
|
| Sulfamethoxazole-Trimethoprim |
800/160 mg |
300 mg QD |
HIV-infected patients (12) |
↔ |
↓ AUC by 15 to 20% |
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| Azithromycin |
500 mg QD x 1 day, then 250 mg QD x 9 days |
300 mg QD |
Healthy subjects (6) |
↔ |
↔ |
|
| Clarithromycin |
500 mg BID |
300 mg QD |
HIV-infected patients (12) |
↑ AUC by 75% |
↓ AUC by 50% |
Monitor for rifabutin associated adverse events. Reduce dose or suspend use of rifabutin if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin |
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| Ethambutol |
1200 mg |
300 mg QD X 7 days |
Healthy subjects (10) |
ND |
↔ |
|
| Isoniazid |
300 mg |
300 mg QD X 7 days |
Healthy subjects (6) |
ND |
↔ |
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| Methadone |
20 to 100 mg QD |
300 mg QD X 13 days |
HIV-infected patients (24) |
ND |
↔ |
|
| Ethinylestradiol (EE)/ Norethindrone (NE) |
35 mg EE / 1 mg NE X 21 days |
300 mg QD X 10 days |
Healthy female subjects (22) |
ND |
EE: ↓ AUC by 35%, ↓ Cmax by 20% NE: ↓ AUC by 46% |
Patients should be advised to use additional or alternative methods of contraception. |
| Theophylline |
5 mg/kg |
300 mg X 14 days |
Healthy subjects (11) |
ND |
↔ |
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Efavirenz (300 mg q24h)** |
Slight Increase in AUCτ |
When voriconazole is coadministered with efavirenz, voriconazole oral |
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AUCτ |
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(CYP3A4 Inhibition) |
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Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
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| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Clarithromycin | 500 twice daily, 7 days |
800 three times daily, 7 days | 12 | 1.19 (1.02, 1.39) |
1.47 (1.30, 1.65) |
1.97 (1.58, 2.46) n=11 |
| Efavirenz | 200 once daily, 14 days |
800 three times daily, 14 days | 20 | No significant change | No significant change | -- |
| Ethinyl Estradiol (ORTHO-NOVUM 1/35) |
35 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.02 (0.96, 1.09) |
1.22 (1.15, 1.30) |
1.37 (1.24, 1.51) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 8 days | 11 | 1.34 (1.12, 1.60) |
1.12 (1.03, 1.22) |
1.00 (0.92, 1.08) |
| Methadone |
20-60 once daily in the morning, 8 days |
800 three times daily, 8 days | 12 | 0.93 (0.84, 1.03) |
0.96 (0.86, 1.06) |
1.06 (0.94, 1.19) |
| Norethindrone (ORTHO-NOVUM 1/35) |
1 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.05 (0.95, 1.16) |
1.26 (1.20, 1.31) |
1.44 (1.32, 1.57) |
| Rifabutin •150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone |
150 once daily in the morning, 10 days 300 once daily in the morning, 10 days |
800 three times daily, 10 days 800 three times daily, 10 days |
14 10 |
1.29 (1.05, 1.59) 2.34 (1.64, 3.35) |
1.54 (1.33, 1.79) 2.73 (1.99, 3.77) |
1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9 |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 4 |
1.61 (1.13, 2.29) |
1.72 (1.20, 2.48) |
1.62 (0.93, 2.85) |
| 200 twice daily, 14 days |
800 twice daily, 14 days |
9, 5 |
1.19 (0.85, 1.66) |
1.96 (1.39, 2.76) |
4.71 (2.66, 8.33) n=9, 4 |
|
| Saquinavir | ||||||
| Hard gel formulation | 600 single dose | 800 three times daily, 2 days | 6 | 4.7 (2.7, 8.1) |
6.0 (4.0, 9.1) |
2.9 (1.7, 4.7) |
| Soft gel formulation | 800 single dose | 800 three times daily, 2 days | 6 | 6.5 (4.7, 9.1) |
7.2 (4.3, 11.9) |
5.5 (2.2, 14.1) |
| Soft gel formulation | 1200 single dose | 800 three times daily, 2 days | 6 | 4.0 (2.7, 5.9) |
4.6 (3.2, 6.7) |
5.5 (3.7, 8.3) |
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| Stavudine |
40 twice daily, 7 days |
800 three times daily, 7 days | 13 | 0.86 (0.73, 1.03) |
1.21 (1.09, 1.33) |
Not Done |
| Theophylline | 250 single dose (on Days 1 and 7) | 800 three times daily, 6 days (Days 2 to 7) | 12, 4 |
0.88 (0.76, 1.03) |
1.14 (1.04, 1.24) |
1.13 (0.86, 1.49) n=7, 3 |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Trimethoprim | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.18 (1.05, 1.32) |
1.18 (1.05, 1.33) |
1.18 (1.00, 1.39) |
| Trimethoprim/ Sulfamethoxazole |
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| Sulfamethoxazole | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.01 (0.95, 1.08) |
1.05 (1.01, 1.09) |
1.05 (0.97, 1.14) |
| Vardenafil | 10 single dose | 800 three times daily | 18 | See text below for discussion of interaction. | ||
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days | 12 | 0.89 (0.73, 1.09) |
1.17 (1.07, 1.29) |
1.51 (0.71, 3.20) n=4 |
| Zidovudine/ Lamivudine |
||||||
| Zidovudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
1.23 (0.74, 2.03) |
1.39 (1.02, 1.89) |
1.08 (0.77, 1.50) n=5, 5 |
| Zidovudine/ Lamivudine |
||||||
| Lamivudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
0.73 (0.52, 1.02) |
0.91 (0.66, 1.26) |
0.88 (0.59, 1.33) |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. | |
| Alcohol | A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase | |
| Allopurinol | Decreases theophylline clearance at doses |
25% increase at allopurinol | |
| Amino glutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease | |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease | |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase | |
| Ciprofloxacin | Similar to cimetidine. | 40% increase | |
| Clarithromycin | Similar to erythromycin. | 25% increase | |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. | |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase | |
| Enoxacin | Similar to cimetidine. | 300% increase | |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. | |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. | |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase | |
| Flurazepam | Similar to diazepam. | Similar to diazepam. | |
| Fluvoxamine | Similar to cimetidine | Similar to cimetidine | |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. | |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase | |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease | |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. | |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. | |
| Lorazepam | Similar to diazepam. | Similar to diazepam. | |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. | |
| Mexiletine | Similar to disulfiram. | 80% increase | |
| Midazolam | Similar to diazepam. | Similar to diazepam. | |
| Moricizine | Increases theophylline clearance. | 25% decrease | |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. | |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase | |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. | |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. | |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. | |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. | |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease | |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease | |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase | |
| Thiabendazole | Decreases theophylline clearance. | 190% increase | |
| Ticlopidine | Decreases theophylline clearance. | 60% increase | |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. | |
| Verapamil | Similar to disulfiram. | 20% increase | |
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| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) |
mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
mg atorvastatin daily |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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Monitor patients with concomitant use of diclofenac sodium topical solution with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of NSAID alone |
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Concomitant use of diclofenac sodium topical solution and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding Diclofenac sodium topical solution is not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDS reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of diclofenac sodium topical solution with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects |
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The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life digoxin. |
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During concomitant use of diclofenac sodium topical solution and digoxin, monitor serum digoxin levels. |
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NSAIDS have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of diclofenac sodium topical solution and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of diclofenac sodium topical solution and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of diclofenac sodium topical solution and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of diclofenac sodium topical solution and cyclosporine, monitor patients for signs or worsening renal function. |
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Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy Concomitant use of oral NSAIDs with diclofenac sodium topical solution has been evaluated in one Phase 3 controlled trial and in combination with oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%) and hemoglobin (13% vs. 9%). |
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The concomitant use of diclofenac with other NSAIDs or salicyclates is not recommended. Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations. |
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Concomitant use of diclofenac sodium topical solution and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of diclofenac sodium topical solution and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
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| albuterol,
systemic and inhaled |
lomefloxacin
mebendazole |
| amoxicillin | medroxyprogesterone |
| ampicillin,
with or without sulbactam |
methylprednisolone
metronidazole |
| atenolol | metoprolol |
| azithromycin | nadolol |
| caffeine,
dietary ingestion |
nifedipine
nizatidine |
| cefactor | norfloxacin |
| co-trimoxazole
(trimethoprim and sulfamethoxazole) |
ofloxacin
omeprazole prednisone, prednisolone |
| diltiazem | ranitidine |
| dirithromycin | rifabutin |
| enflurane | roxithromycin |
| famotidine | sorbitol |
| felodipine
finasteride hydrocortisone |
(purgative doses do not
inhibit theophylline absorption) |
| isoflurane | sucralfate |
| isoniazid | terbutaline, systemic |
| isradipine | terfenadine |
| influenza vaccine | tetracycline |
| ketoconazole | tocainide |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| Dopamine / Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
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| Aminoglutethimide
Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone
Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4, and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. |
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| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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|
Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
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|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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|
|
|
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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|
|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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|
|
|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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|
|
| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| |
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. |
| |
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
| |
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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| |
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
| |
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Oral Solution if serotonin syndrome is suspected. |
| |
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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| |
MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) |
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|
Do not use Morphine Sulfate Oral Solution in patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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| |
May reduce the analgesic effect of Morphine Sulfate Oral Solution and/or precipitate withdrawal symptoms. |
| |
Avoid concomitant use. |
| |
butorphanol, nalbuphine, pentazocine, buprenorphine, |
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| |
Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
| |
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Oral Solution and/or the muscle relaxant as necessary. |
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| |
The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report. |
| |
Monitor patients for increased respiratory and CNS depression when Morphine Sulfate Oral Solution is used concomitantly with cimetidine. |
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| |
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
| |
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
| |
|
| |
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
| |
Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Oral Solution is used concomitantly with anticholinergic drugs. |
| |
|
| |
The concomitant use of P-gp inhibitors can increase the exposure to morphine by two-fold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
| |
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Oral Solution and/or the P-gp inhibitor as necessary. |
|
|
quinidine, verapamil |
|
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|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose (5.12, |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Darunavir or Concomitant Drug | Clinical Comment |
|---|---|---|
|
|
||
| didanosine | ↔ darunavir ↔ didanosine |
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food). |
|
|
||
| indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.) |
↑ darunavir ↑ indinavir |
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established. |
| lopinavir/ritonavir | ↓ darunavir ↔ lopinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir. |
| saquinavir | ↓ darunavir ↔ saquinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir. |
|
|
||
| Maraviroc | ↑ maraviroc | Maraviroc concentrations are increased when co-administered with PREZISTA/rtv. When used in combination with PREZISTA/rtv, the dose of maraviroc should be 150 mg twice daily. |
|
|
||
|
bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone |
↑ antiarrhythmics | Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir. |
| digoxin | ↑ digoxin | The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect. |
|
warfarin |
↓ warfarin ↔ darunavir |
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir. |
|
carbamazepine |
↔ darunavir ↑ carbamazepine |
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response. |
|
phenobarbital, phenytoin |
↔ darunavir ↓ phenytoin ↓ phenobarbital |
Co-administration of PREZISTA/ritonavir may cause decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir. |
|
trazodone, desipramine |
↑ trazodone ↑ desipramine |
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution and a lower dose of trazodone or desipramine should be considered. |
|
clarithromycin |
↔ darunavir ↑ clarithromycin |
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered:
|
|
ketoconazole, itraconazole, voriconazole |
↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied) |
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir. |
| Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg. | ||
| Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole. | ||
|
colchicine |
↑ colchicine |
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir. |
|
rifabutin |
↑ darunavir ↑ rifabutin ↑ 25- |
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary. |
| The reference regimen for rifabutin was 300 mg once daily | ||
|
metoprolol, timolol |
↑ beta-blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
|
parenterally administered midazolam |
↑ midazolam | Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED. |
|
felodipine, nifedipine, nicardipine |
↑ calcium channel blockers | Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended. |
|
dexamethasone |
↓ darunavir | Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. |
|
fluticasone |
↑ fluticasone | Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long term use. |
|
bosentan |
↑ bosentan |
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
pravastatin, atorvastatin, rosuvastatin |
↑ pravastatin ↑ atorvastatin ↑ rosuvastatin |
Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/ritonavir. |
|
cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir. |
|
salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
|
methadone, buprenorphine, buprenorphine/naloxone |
↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite) |
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered. |
|
risperidone, thioridazine |
↑ neuroleptics | A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
|
ethinyl estradiol, norethindrone |
↓ ethinyl estradiol ↓ norethindrone |
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended. |
|
sildenafil, vardenafil, tadalafil |
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) |
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events. |
|
sertraline, paroxetine |
↔ darunavir ↓ sertraline ↓ paroxetine |
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response. |
|
|
|||||
| Coadministered Drug
|
Dosing Schedule
|
Effect on Active
Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose
Recommendation |
||
|
|
Coadministered Drug
|
Risperidone
|
AUC
|
Cmax
|
|
| Enzyme (CYP2D6)
Inhibitors |
|
|
|
|
|
| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice
daily |
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day
|
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
|
Re-evaluate dosing.
|
|
|
20 mg/day
|
4 mg/day
|
1.6
|
|
Do not exceed 8 mg/day
|
|
|
40 mg/day
|
4 mg/day
|
1.8
|
|
|
| Enzyme (CYP3A/ PgP inducers) Inducers
|
|
|
|
|
|
| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards.
Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)
Inhibitors |
|
|
|
|
|
| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not
needed |
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not
needed |
| Erythromycin
|
500 mg four times
daily |
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not
needed |
|
|
|
|
|
|
|
| Other Drugs
|
|
|
|
|
|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not
needed |
|
|
|
|
|---|---|---|
|
a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b= Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated |
||
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|
|
| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin | Monitor phenytoin level ( |
| Methotrexate | Monitor for methotrexate toxicity ( |
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine | Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( |
| Increased Risk of Myopathy/Rhabdomyolysis ( |
|
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| Lopinavir plus ritonavir | Use lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
| Antiarrhythmics | digoxin, dofetilide, quinidine, disopyramide |
| Anticonvulsants | carbamazepine |
| Anti-HIV Agents | indinavir, ritonavir, saquinavir, maraviroc |
| Antineoplastics | busulfan, docetaxel, vinca alkaloids |
| Antipsychotics | pimozide |
| Benzodiazepines | alprazolam, diazepam, midazolam, |
| Calcium Channel Blockers | dihydropyridines (including nisoldipine and felodipine), verapamil |
| Gastrointestinal Motility Agents | cisapride |
| HMG CoA-Reductase Inhibitors | atorvastatin, cerivastatin, lovastatin, simvastatin |
| Immunosuppressants | Cyclosporine, tacrolimus, sirolimus |
| Oral Hypoglycemics | oral hypoglycemics (repaglinide) |
| Opiate Analgesics | fentanyl, levacetylmethadol (levomethadyl), methadone |
| Polyene Antifungals | amphotericin B |
| Other | ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, warfarin, cilostazol, eletriptan, fexofenadine, loperamide |
|
|
|
| Anticonvulsants | carbamazepine, phenobarbital, phenytoin |
| Anti-HIV Agents | nevirapine, efavirenz |
| Antimycobacterials | isoniazid, rifabutin, rifampin |
| Gastric Acid Suppressors/Neutralizers | antacids, H2-receptor antagonists, proton pump inhibitors |
|
|
|
| Macrolide Antibiotics | clarithromycin, erythromycin |
| Anti-HIV Agents | indinavir, ritonavir |
|
|
|
| Prothrombin time (PT) up to 12 hours | Chromogenic Factor Xa Assay |
| International normalized ratio (INR) up to 12 hours | Thrombin Time (TT) |
| Activated partial thromboplastin time (aPTT) up to 120 hours | |
| Activated clotting time (ACT) up to 24 hours | |
| Silica clot time (SCT) up to 18 hours | |
| Dilute Russell’s viper venom time (DRVVT) up to 72 hours | |
| D-dimer up to 72 hours |
| *This list is not all-inclusive. | |
| |
|
| Carbamazepine | Phenytoin |
| Gastric Acid Suppressants (antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors, sucralfate) | Rifampin, rifabutin, isoniazid |
| Nevirapine | |
| |
|
| Ritonavir | |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
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|
|
|||
| Aminoglutethimide
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone
Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
|
|
The concomitant use of HYSINGLA
ER and CYP3A4 inhibitors can increase the plasma concentration of
hydrocodone, resulting in increased or prolonged opioid effects. These
effects could be more pronounced with concomitant use of HYSINGLA
ER and CYP3A4 inhibitors, particularly when an inhibitor is added
after a stable dose of HYSINGLA ER is achieved After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease |
|
|
If concomitant use is necessary,
consider dosage reduction of HYSINGLA ER until stable drug effects
are achieved. Monitor patients for respiratory depression and sedation
at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the HYSINGLA ER dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
|
|
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
|
|
|
|
|
The concomitant use of HYSINGLA
ER and CYP3A4 inducers can decrease the plasma concentration of hydrocodone After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase |
|
|
If concomitant use is necessary, consider increasing the HYSINGLA ER dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider HYSINGLA ER dosage reduction and monitor for signs of respiratory depression. |
|
|
Rifampin, carbamazepine, phenytoin |
|
|
|
|
|
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
|
|
Reserve concomitant prescribing
of these drugs for use in patients for whom alternative treatment
options are inadequate. Limit dosages and durations to the minimum
required. Follow patients closely for signs of respiratory depression
and sedation |
|
|
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
|
|
|
|
|
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
|
|
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue HYSINGLA ER if serotonin syndrome is suspected. |
|
|
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
|
|
|
|
|
MAOI interactions with opioids
may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory
depression, coma) |
|
|
The use of HYSINGLA ER is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
|
|
Phenelzine, tranylcypromine, linezolid |
|
|
|
|
|
May reduce the analgesic effect of HYSINGLA ER and/or precipitate withdrawal symptoms. |
|
|
Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of HYSINGLA ER and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when HYSINGLA ER is used concomitantly with anticholinergic drugs. |
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Concomitant use of HYSINGLA ER with strong laxatives that rapidly increase gastrointestinal motility, may decrease hydrocodone absorption and result in decreased hydrocodone plasma levels. |
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If HYSINGLA ER is used in these patients, closely monitor for the development of adverse events as well as changing analgesic requirements. |
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Lactulose |
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| Anticoagulants
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argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
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| Antiplatelet Agents
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aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
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| Nonsteroidal Anti-Inflammatory Agents
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celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
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| Serotonin Reuptake Inhibitors
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citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone
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| Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements. | |
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| Phenobarbital
Rifampin |
Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine. |
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| Multivalent cation-containing products including: antacids, sucralfate, multivitamins |
Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. ( |
| Class IA and Class III antiarrhythmics: |
Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
| Antidiabetic agents |
Carefully monitor blood glucose. ( |
| Drug/Drug Class (Mechanism of Interaction by the Drug) |
Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg q12h) |
Recommendations for Voriconazole Dosage Adjustment/Comments |
|---|---|---|
| Rifampin (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (400 mg q24h) (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (300 mg q24h) (CYP450 Induction) |
Slight Decrease in AUC |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
Significantly Reduced |
|
| Low-dose Ritonavir (100 mg q12h) |
Reduced | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John's Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole |
Significantly Increased | Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir |
|
|
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
|
| Other NNRTIs (CYP3A4 Inhibition or CYP450 Induction) |
|
Frequent monitoring for adverse events and toxicity related to voriconazole |
| A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Careful assessment of voriconazole effectiveness |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Interacting Drug | Interaction |
|---|---|
| Valproic acid | Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects ( |
| Probenecid | Reduces renal clearance of doripenem, resulting in increased doripenem concentrations ( |
| Drugs metabolized by cytochrome P450 enzymes | Doripenem neither inhibits nor induces major cytochrome P450 enzymes ( |
|
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|||
| Cmax | AUC 0–24 hrs |
Cmax | AUC 0–24 hrs |
|
| Erythromycin (500 mg Q8h) |
+24% | +14% | +43% | +40% |
| Ketoconazole (200 mg Q12h) |
+45% | +39% | +43% | +72% |
| Azithromycin (500 mg day 1, 250 mg QD × 4 days) |
+15% | +5% | +15% | +4% |
| Fluoxetine (20 mg QD) |
+15% | +0% | +17% | +13% |
| Cimetidine (600 mg Q12h) |
+12% | +19% | -11% | -3% |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| ↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data. |
||
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
|
|
|
| Known CYP2D6 Poor Metabolizers |
Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors |
Administer a quarter of usual dose |
| Strong CYP2D6 |
Administer half of usual dose |
| Strong CYP2D6 |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers |
Double usual dose over 1 to 2 weeks |
|
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|
| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
| |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
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|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
| |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
|---|---|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Rilpivirine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↑ = increase, ↓ = decrease, ↔ = no change |
||
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|
||
| didanosine |
↔ rilpivirine ↔ didanosine |
No dose adjustment is required when EDURANT is co-administered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after EDURANT (which should be administered with a meal). |
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||
| NNRTI (delavirdine) |
↑ rilpivirine ↔ delavirdine |
It is not recommended to co-administer EDURANT with delavirdine and other NNRTIs. |
| Other NNRTIs (efavirenz, etravirine, nevirapine) |
↓ rilpivirine ↔ other NNRTIs |
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| darunavir/ritonavir |
↑ rilpivirine ↔ boosted darunavir |
Concomitant use of EDURANT with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with darunavir/ritonavir. |
| lopinavir/ritonavir |
↑ rilpivirine ↔ boosted lopinavir |
Concomitant use of EDURANT with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with lopinavir/ritonavir. |
| other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) | ↑ rilpivirine ↔ boosted PI |
Concomitant use of EDURANT with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs. |
| unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir) | ↑ rilpivirine ↔ unboosted PI |
Concomitant use of EDURANT with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs. |
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|
antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate) |
↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) |
The combination of EDURANT and antacids should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after EDURANT. |
| ↓ rilpivirine (concomitant intake) |
||
|
rifabutin |
↓ rilpivirine | Concomitant use of EDURANT with rifabutin may cause a decrease in the plasma concentrations of rilpivirine (induction of CYP3A enzymes). Throughout co-administration of EDURANT with rifabutin, the EDURANT dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg once daily. |
|
fluconazole itraconazole ketoconazole posaconazole voriconazole |
↑ rilpivirine ↓ ketoconazole |
Concomitant use of EDURANT with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when EDURANT is co-administered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are co-administered with EDURANT. |
|
cimetidine famotidine nizatidine ranitidine |
↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) |
The combination of EDURANT and H2-receptor antagonists should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after EDURANT. |
| ↓ rilpivirine (famotidine taken 2 hours before rilpivirine) |
||
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clarithromycin erythromycin telithromycin |
↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin |
Concomitant use of EDURANT with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered. |
|
methadone |
↓ R(-) methadone ↓ S(+) methadone |
No dose adjustments are required when initiating co-administration of methadone with EDURANT. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
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See prescribing information for voriconazole. |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Atazanavir/ Ritonavir* |
¯ Atazanavir Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
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| Fosamprenavir* |
¯Amprenavir Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
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| Fosamprenavir/ Ritonavir* |
¯Amprenavir Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
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| Indinavir* |
¯ Indinavir |
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
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| Lopinavir/ Ritonavir* |
¯Lopinavir |
Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
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Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight.Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
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| Nelfinavir* |
¯Nelfinavir M8 Metabolite ¯Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
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| Saquinavir/ Ritonavir |
The interaction between nevirapine saquinavir/ritonavir has not been evaluated |
The appropriate doses of the combination of and nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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| Drug Name |
Effect on Concentration of Nevirapine or Concomitant Drug |
Clinical Comment |
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| Efavirenz* |
¯ Efavirenz |
The appropriate doses of these combinations with respect to safety and efficacy have not been established. |
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| Delavirdine Etravirine Rilpivirine |
|
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
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| Boceprevir |
Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine |
Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy. |
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| Telaprevir |
Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. |
Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may be may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events. |
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Methadone* |
¯ Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
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|
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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Clarithromycin* |
¯ Clarithromycin 14-OH clarithromyci |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
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| Rifabutin* |
Rifabutin |
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
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| Drug Name |
Effect on Concentration of Nevirapine or Concomitant Drug |
Clinical Comment |
||
| Rifampin* |
¯ Nevirapine |
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
||
| Anticonvulsants: Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
||
| Antifungals: Fluconazole* |
Nevirapine |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
||
| Ketoconazole* |
¯ Ketoconazole |
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
||
| Itraconazole |
¯ Itraconazole |
Nevirapine and itraconazole should not be administered concomitantly due to potentia decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
||
| Antithrombotics: Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
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| Calcium channel blockers: Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
||
| Cancer chemotherapy: Cyclophosphamide |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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| Ergot alkaloids: Ergotamine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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| Immunosuppressants: Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
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| Motility agents: Cisapride |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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| Opiate agonists: Fentanyl |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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| Oral contraceptives: Ethinyl estradiol and Norethindrone* |
¯Ethinyl estradiol ¯ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
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| * The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. |
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| Clinical Impact: | Decreased exposure of omeprazole when used concomitantly with strong inducers [see |
| Intervention: | St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see |
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| Clinical Impact: | Increased exposure of omeprazole [see |
| Intervention: | Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole. |
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| *Refer to | |||
| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. | |
| Alcohol | A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase | |
| Allopurinol | Decreases theophylline clearance at allopurinol doses | 25% increase | |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease | |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease | |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase | |
| Ciprofloxacin | Similar to cimetidine. | 40% increase | |
| Clarithromycin | Similar to erythromycin. | 25% increase | |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. | |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase | |
| Enoxacin | Similar to cimetidine. | 300% increase | |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. | |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. | |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase | |
| Flurazepam | Similar to diazepam. | Similar to diazepam. | |
| Fluvoxamine | Similar to cimetidine | Similar to cimetidine | |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. | |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase | |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease | |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. | |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. | |
| Lorazepam | Similar to diazepam. | Similar to diazepam. | |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. | |
| Mexiletine | Similar to disulfiram. | 80% increase | |
| Midazolam | Similar to diazepam. | Similar to diazepam. | |
| Moricizine | Increases theophylline clearance. | 25% decrease | |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. | |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase | |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. | |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. | |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. | |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. | |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease | |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease | |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase | |
| Thiabendazole | Decreases theophylline clearance. | 190% increase | |
| Ticlopidine | Decreases theophylline clearance. | 60% increase | |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. | |
| Verapamil | Similar to disulfiram. | 20% increase | |
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| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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|---|---|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. | |
| Alcohol | A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase | |
| Allopurinol | Decreases theophylline clearance at allopurinol doses 600 mg/day.
|
25% increase | |
| Amino glutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease | |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease | |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase | |
| Ciprofloxacin | Similar to cimetidine. | 40% increase | |
| Clarithromycin | Similar to erythromycin. | 25% increase | |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. | |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase | |
| Enoxacin | Similar to cimetidine. | 300% increase | |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. | |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. | |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase | |
| Flurazepam | Similar to diazepam. | Similar to diazepam. | |
| Fluvoxamine | Similar to cimetidine | Similar to cimetidine | |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. | |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase | |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease | |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. | |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. | |
| Lorazepam | Similar to diazepam. | Similar to diazepam. | |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. | |
| Mexiletine | Similar to disulfiram. | 80% increase | |
| Midazolam | Similar to diazepam. | Similar to diazepam. | |
| Moricizine | Increases theophylline clearance. | 25% decrease | |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. | |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase | |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. | |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. | |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. | |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. | |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease | |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease | |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase | |
| Thiabendazole | Decreases theophylline clearance. | 190% increase | |
| Ticlopidine | Decreases theophylline clearance. | 60% increase | |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. | |
| Verapamil | Similar to disulfiram. | 20% increase | |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( |
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Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology ( |
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During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. |
|
| Allopurinol |
|
25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. |
|
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increase theophylline clearance. | 20% increase |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20 to 40% decrease |
| Sulfinpyrazone | Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% increase |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33 to 100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
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| Dopamine/Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
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|||
| Amiodarone
Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. | ||
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| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (
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Avoid atorvastatin
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| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
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Do not exceed 20 mg atorvastatin daily
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| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Coadministered Drug | Dosing Schedule | Effect on Active
Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose
Recommendation |
||
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6)
Inhibitors |
|||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice
daily |
1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. |
| 20 mg/day | 4 mg/day | 1.6 | - | Do not exceed 8 mg/day | |
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/
PgP inducers) |
|||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards.
Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)
Inhibitors |
|||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not
needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not
needed |
| Erythromycin | 500 mg four times
daily |
1 mg single dose | 1.1 | 0.94 | Dose adjustment not
needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not
needed |
| Classes of Drugs | |||
| 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials |
Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors† |
Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins† |
|
| CYP2C19 or CYP3A4 Inducers |
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Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( |
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St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings And Precautions ( |
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Increased exposure of omeprazole [see Clinical Pharmacology ( |
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Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole. |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Antiarrhythmics: |
|||||
| Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide |
Not Recommended |
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
|||
| Digoxin | Use With Caution |
|
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| Oral Anticoagulants: |
|||||
| Warfarin | Use With Caution |
|
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| Antiepileptics: |
|||||
| Carbamazepine | Use With Caution |
|
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| Antifungals: |
|||||
| Itraconazole | Use With Caution |
|
|||
| Fluconazole | No Dose Adjustment |
|
|||
| Anti-Gout Agents: |
|||||
| Colchicine (in patients with renal or hepatic impairment) |
Contraindicated |
|
|||
| Colchicine (in patients with normal renal and hepatic function) | Use With Caution | ||||
| Antipsychotics: |
|||||
| Pimozide | Contraindicated |
|
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| Quetiapine |
|
||||
| Antispasmodics: |
|||||
| Tolterodine (patients deficient in CYP2D6 activity) | Use With Caution |
|
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| Antivirals: |
|||||
| Atazanavir | Use With Caution |
|
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| Saquinavir (in patients with decreased renal function) |
|
||||
| Ritonavir Etravirine |
|
||||
| Maraviroc |
|
||||
| Boceprevir (in patients with normal renal function) Didanosine |
No Dose Adjustment |
|
|||
| Zidovudine |
The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated. |
||||
| Calcium Channel Blockers: |
|||||
| Verapamil | Use With Caution |
|
|||
| Amlodipine Diltiazem |
|
||||
| Nifedipine |
|
||||
| Ergot Alkaloids: |
|||||
| Ergotamine Dihydroergotamine |
Contraindicated |
|
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| Gastroprokinetic Agents: |
|||||
| Cisapride | Contraindicated |
|
|||
| HMG-CoA Reductase Inhibitors: |
|||||
| Lovastatin Simvastatin |
Contraindicated |
|
|||
| Atorvastatin Pravastatin |
Use With Caution | ||||
| Fluvastatin |
No Dose Adjustment |
||||
| Hypoglycemic Agents: |
|||||
| Nateglinide Pioglitazone Repaglinide Rosiglitazone |
Use With Caution |
|
|||
| Insulin |
|
||||
| Immunosuppressants: |
|||||
| Cyclosporine | Use With Caution |
|
|||
| Tacrolimus |
|
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| Phosphodiesterase inhibitors: |
|||||
| Sildenafil Tadalafil Vardenafil |
Use With Caution |
|
|||
| Proton Pump Inhibitors: |
|||||
| Omeprazole | No Dose Adjustment |
|
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| Xanthine Derivatives: |
|||||
| Theophylline | Use With Caution |
|
|||
| Triazolobenzodiazepines and Other Related Benzodiazepines: |
|||||
| Midazolam | Use With Caution |
|
|||
| Alprazolam Triazolam |
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
||||
| Temazepam Nitrazepam Lorazepam |
No Dose Adjustment |
|
|||
| Cytochrome P450 Inducers: |
|||||
| Rifabutin | Use With Caution |
|
|||
| Other Drugs Metabolized by CYP3A: |
|||||
| Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution | There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. | |||
| Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: |
|||||
| Hexobarbital Phenytoin Valproate |
Use With Caution | There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. |
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|||
| Antifungals: |
|||||
| Itraconazole |
Use With Caution |
|
|||
| Antivirals: |
|||||
| Atazanavir | Use With Caution |
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to |
|||
| Ritonavir (in patients with decreased renal function) |
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. |
||||
| Saquinavir (in patients with decreased renal function) |
|
||||
| Etravirine |
|
||||
| Saquinavir (in patients with normal renal function) |
No Dose Adjustment | ||||
| Ritonavir (in patients with normal renal function) |
|||||
| Proton Pump Inhibitors: |
|||||
| Omeprazole | Use With Caution |
|
|||
| Miscellaneous Cytochrome P450 Inducers: |
|||||
| Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine |
Use With Caution | Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see |
|||
|
albuterol, systemic and inhaled |
mebendazole |
|
amoxicillin |
medroxyprogesterone |
|
ampicillin, with or without |
methylprednisolone |
|
sulbactam |
metronidazole |
|
atenolol |
metoprolol |
|
azithromycin |
nadolol |
|
caffeine, dietary ingestion |
nifedipine |
|
cefaclor |
nizatidine |
|
co-trimoxazole (trimethoprim and sulfamethoxazole) |
norfloxacin |
|
ofloxacin |
|
|
diltiazem |
omeprazole |
|
dirithromycin |
prednisone, prednisolone |
|
enflurane |
ranitidine |
|
famotidine |
rifabutin |
|
felodipine |
roxithromycin |
|
finasteride |
Sorbitol (purgative doses do not inhibit |
|
hydrocortisone |
theophylline absorption) |
|
isoflurane |
sucralfate |
|
isoniazid |
terbutaline, systemic |
|
isradipine |
terfenadine |
|
influenza vaccine |
tetracycline |
|
ketoconazole |
tocainide |
|
lomefloxacin |
|
| |
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||
| |
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||
| |
400 mg/day for 5 days |
10 mg single dose |
6.9-times LATUDA alone |
9-times LATUDA alone |
Should not be coadministered with LATUDA |
| |
240 mg/ day for 5 days |
20 mg single dose |
2.1- times LATUDA alone |
2.2- times LATUDA alone |
LATUDA dose should not exceed 40 mg/day if coadministered |
| |
600 mg/day for 8 days |
40 mg single dose |
1/7th of LATUDA alone | 1/5th of LATUDA alone | Should not be coadministered with LATUDA |
| |
600 mg BID for 8 days |
120 mg/day for 8 days |
0.9-times LATUDA alone | 1.1- times LATUDA alone | No LATUDA dose adjustment required. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
|
|
|
|
|
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole |
melphalan | amphotericin B ketoconazole |
azapropazon colchicine diclofenac naproxen sulindac |
|
|
|
|
|
| cimetidine ranitidine |
tacrolimus | fibric acid derivatives (e.g. bezafibrate, fenofibrate) methotrexate |
|
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary digestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
|
|
|
| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
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||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine |
Decreased lamotrigine levels approximately 50% |
|
|
↓ levonorgestrel |
Decrease in levonorgestrel component by 19% |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine |
Addition of carbamazepine decreases lamotrigine concentration approximately 40% |
|
|
? CBZ epoxide |
May increase CBZ epoxide levels. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40% |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40% |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40% |
| Valproate |
↑ lamotrigine |
Increased lamotrigine concentrations slightly more than 2-fold |
|
|
? valproate |
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| |
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
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|---|---|
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See prescribing information for voriconazole. |
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|
| Thyroid Function | Decreased PBI; increased T3 uptake |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd) |
| 5 Hydroxyindole acetic acid | False negative with fluorometric test |
| Acetone, Ketone Bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling |
| 17-OH corticosteroids | False reduced values with >4.8 g qd salicylate |
| Vanilmandelic Acid | False reduced values |
| Uric Acid | May increase or decrease depending on dose |
| Prothrombin | Decreased levels; slightly increased prothrombin time |
|
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
|
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|
- Coumarin Derivatives - Indandione Derivatives |
|
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
|
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose |
|
|
|
|
Multivalent cation-containing products including antacids, metal cation or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. |
|
Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
|
Antidiabetic agent |
Carefully monitor blood glucose ( |
| Classes of Drugs | ||
| Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†
|
Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†
|
Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†
|
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Monitor patients with concomitant use of MOBIC with anticoagulants
(e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin
reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake
inhibitors (SNRIs) for signs of bleeding [ |
|
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|
|
Controlled clinical studies showed that the concomitant
use of NSAIDs and analgesic doses of aspirin does not produce any
greater therapeutic effect than the use of NSAIDs alone. In a clinical
study, the concomitant use of an NSAID and aspirin was associated
with a significantly increased incidence of GI adverse reactions as
compared to use of the NSAID alone [ |
|
|
Concomitant
use of MOBIC and low dose aspirin or analgesic doses of aspirin is
not generally recommended because of the increased risk of bleeding
[ MOBIC is not a substitute for low dose aspirin for cardiovascular protection. |
|
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
|
|
During concomitant use of MOBIC with diuretics, observe
patients for signs of worsening renal function, in addition to assuring
diuretic efficacy including antihypertensive effects [ |
|
|
|
|
|
NSAIDs have produced elevations in plasma lithium levels
and reductions in renal lithium clearance. The mean minimum lithium
concentration increased 15%, and the renal clearance decreased by
approximately 20%. This effect has been attributed to NSAID inhibition
of renal prostaglandin synthesis [ |
|
|
During concomitant use of MOBIC and lithium, monitor patients for signs of lithium toxicity. |
|
|
|
|
|
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
|
|
During concomitant use of MOBIC and methotrexate, monitor patients for methotrexate toxicity. |
|
|
|
|
|
Concomitant use of MOBIC and cyclosporine may increase cyclosporine's nephrotoxicity. |
|
|
During concomitant use of MOBIC and cyclosporine, monitor patients for signs of worsening renal function. |
|
|
|
|
|
Concomitant use of meloxicam with other NSAIDs or salicylates
(e.g., diflunisal, salsalate) increases the risk of GI toxicity, with
little or no increase in efficacy [ |
|
|
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
|
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|
|
|
Concomitant use of MOBIC and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
|
|
During concomitant use of MOBIC and pemetrexed, in patients
with renal impairment whose creatinine clearance ranges from 45 to
79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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|
Cases of intestinal necrosis (possibly fatal) have been described in patients who received concomitant sorbitol and Kayexalate® (sodium polystyrene sulfonate). Due to the presence of sorbitol in MOBIC Oral Suspension, use with Kayexalate® is not recommended. |
|
|
The concomitant use of MOBIC Oral Suspension with Kayexalate® is not recommended. |
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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Hepatitis C Protease inhibitor (boceprevir) |
|
| *Change relative to reference
|
|||||
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Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Recommendation |
||
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Inhibitors |
|||||
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daily |
|
|
exceed 8 mg/day |
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PgP inducers) |
|||||
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Do not exceed twice the patient’s usual dose |
|
Inhibitors |
|||||
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needed |
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needed |
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daily |
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needed |
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|||||
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needed |
| Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours |
Simultaneous dosing of Vardenafil and Alpha-Blocker |
||||
| Alpha-Blocker | Vardenafil 10 mg Placebo-Subtracted |
Vardenafil 20 mg Placebo-Subtracted |
Vardenafil 10 mg Placebo-Subtracted |
Vardenafil 20 mg Placebo-Subtracted |
|
| Terazosin 10 mg daily |
Standing SBP | -7 (-10, -3) | -11 (-14, -7) | -23 (-31, 16) |
-14 (-33, 11) |
| Supine SBP | -5 (-8, -2) | -7 (-11, -4) | -7 (-25, 19) |
-7 (-31, 22) |
|
| Tamsulosin 0.4 mg daily |
Standing SBP | -4 (-8, -1) | -8 (-11, -4) | -8 (-14, -2) | -8 (-14, -1) |
| Supine SBP | -4 (-8, 0) | -7 (-11, -3) | -5 (-9, -2) | -3 (-7, 0) | |
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|---|---|---|---|---|
|
1 nc denotes a mean change of less than 10% 2 Pediatrics 3 Mean increase in adults at high oxcarbazepine tablets doses |
||||
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>1200-2400 |
up to 40% increase3 [CI: 12% increase, 60% increase] |
[CI: 3% decrease, 48% decrease] |
|
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|
|
Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
|
Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see
|
|
|
|
|
|
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone
|
|
|
Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see
Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection. |
|
|
|
|
|
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
|
| In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
|
|
|
|
During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
|
| During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function
|
|
| When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
|
|
|
|
|
|
|
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
|
|
|
During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects
|
|
|
|
|
|
The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
|
|
|
During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels.
|
|
|
|
|
|
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
|
|
|
During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity.
|
|
|
|
|
|
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
|
|
|
During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity.
|
|
|
|
|
|
Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity.
|
|
|
During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function.
|
|
|
|
|
|
Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy
|
|
|
The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended.
|
|
|
|
|
|
Concomitant use of mefenamic acid and pemetrexed may increase the risk of pemetrexedassociated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
|
|
|
During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
|
| NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
|
|
| In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
|
|
|
|
|
|
|
In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the C
max and AUC of mefenamic acid by 125% and 36%, respectively.
|
|
|
Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events.
|
|
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|
|
The concomitant use of ABSTRAL and CYP3A4 inhibitors can increase the plasma concentration of fentanyl resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of ABSTRAL is achieved After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease |
|
|
If concomitant use is necessary, consider dosage reduction of ABSTRAL until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the ABSTRAL dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
|
|
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) grapefruit juice. |
|
|
|
|
|
The concomitant use of ABSTRAL with CYP3A4 inducers can decrease the plasma concentrations of fentanyl After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase |
|
|
If concomitant use is necessary, consider increasing the ABSTRAL dosage until stable drug effects are achieved Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider ABSTRAL dosage reduction and monitor for signs of respiratory depression. |
|
|
rifampin, carbamazepine, phenytoin |
|
|
|
|
|
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death. |
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|
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation, |
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|
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [ |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ABSTRAL if serotonin syndrome is suspected. |
|
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome |
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The use of ABSTRAL is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of ABSTRAL and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of ABSTRAL and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on bloodpressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motilitywhen ABSTRAL is used concomitantly with anticholinergic drugs. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide
|
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 | ||
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|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
|
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
|
||
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|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 | ||
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|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 | ||
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|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| DRUG | DESCRIPTION OF INTERACTION |
| Sulfonylureas | Hypoglycemia potentiated. |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. |
|
|
Increased bleeding. |
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|
|---|---|---|
| ↑ Indicates increase. ↓ Indicates decrease. a Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. |
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| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*) | Risperidone Dose Recommendation | ||
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
|
|
|
| Multivalent cation-containing products including antacids, metal cation or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agent | Carefully monitor blood glucose ( |
| Concomitant Drug Name or Drug Class |
Clinical Rationale and Magnitude of Drug Interaction | Clinical Recommendation |
| Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure |
Consider dose reduction |
| Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure |
Consider dose increase |
|
Drug Name |
on Paroxetine |
|
| Phenobarbital
|
Decreased paroxetine exposure
|
|
|
Phenytoin |
Decreased paroxetine exposure
|
|
|
Fosamprenavir/ Ritonavir |
Decreased plasma concentration
of paroxetine |
No dose adjustment for BRISDELLE.
Monitor clinical effect of BRISDELLE. |
| Cimetidine | Increased plasma concentration
of paroxetine |
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|
Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole. |
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|
Dose adjustment of Paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor. |
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Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol. |
|
|
Recommend to take Paricalcitol capsules at least 1 hour |
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|
Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol. |
|
|
Recommend to take Paricalcitol capsules at least 1 hour |
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| Multivalent cationcontaining products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Concomitant Drug | Effect on Concentration of Lamotrigine or
Concomitant Drug |
Clinical Comment |
|
|
||
| Estrogen-containing oral
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine
|
Decreased lamotrigine levels
approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and
CBZ epoxide |
↓ lamotrigine
|
Addition of carbamazepine decreases lamotrigine
concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine
concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine
concentration approximately 40% |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC
approximately 40% |
| Valproate | ↑ lamotrigine
|
Increased lamotrigine concentrations slightly
more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia |
| Uricosuric Agents | Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited |
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| Known CYP2D6 Poor Metabolizers | Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP2D6
|
Administer half of usual dose |
| Strong CYP2D6
|
Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
|
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|
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
|
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|
|
| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
|
|
Concentration of Lamotrigine or Concomitant Drug |
|
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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|
| Tizanidine |
Contraindicated |
Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline |
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate |
| Drugs Known to Prolong QT Interval |
Avoid Use |
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs |
Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin |
Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine |
Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs |
Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate |
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole |
Use with caution |
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin |
| Clozapine |
Use with caution |
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs |
Use with caution |
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil |
Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine |
Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
|
|
||
| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Probenecid |
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
|
| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
| |
|
| Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). | Quinine sulfate prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use |
| Other antimalarials (e.g., halofantrine, mefloquine). | ECG abnormalities including QT prolongation. Avoid concomitant use |
| CYP3A4 inducers or inhibitors | Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine |
| CYP3A4 and CYP2D6 substrates | Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug |
| Digoxin | Increased digoxin plasma concentration |
| Drug/Drug Class (Mechanism of Interaction by Voriconazole) |
Drug Plasma Exposure (Cmax and AUCτ) |
Recommendations for Drug Dosage Adjustment/Comments |
|---|---|---|
| Sirolimus (CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (400 mg q24h) (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (300 mg q24h) (CYP3A4 Inhibition) |
Slight Increase in AUCτ | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ |
|
| Low-dose Ritonavir (100 mg q12h) |
Slight Decrease in Ritonavir Cmax and AUCτ | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
|
| Cyclosporine (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) |
Increased | Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary |
| Oxycodone (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary |
| NSAIDs (CYP2C9 Inhibition) |
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed |
| Tacrolimus (CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin (CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole (CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment for indinavir when coadministered with VFEND |
|
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors | |
| Other NNRTIs (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
| Everolimus (CYP3A4 Inhibition) |
Not Studied |
Concomitant administration of voriconazole and everolimus is not recommended. |
|
|
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|
|
|
||
| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – Antagonist: maraviroc |
↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
|
|
||
| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers: dihydropyridine, felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Long-acting beta-adrenoceptor Agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
| * |
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|
| CYP2C9
|
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
|
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
|
| CYP1A2
|
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
|
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
|
| CYP3A4
|
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
|
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide
|
|
(Mechanism of Interaction by the Drug) |
(Cmax and AUCτ after 200 mg q12h) |
|
|---|---|---|
| Rifampin (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (400 mg q24h)†
(CYP450 Induction) Efavirenz (300 mg q24h)† (CYP450 Induction) |
Significantly Reduced Slight Decrease in AUCτ |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High dose Ritonavir (400 mg q12h)†
(CYP450 Induction) Low dose Ritonavir (100 mg q12h)† (CYP450 Induction) |
Significantly Reduced Reduced |
Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied to Result in Significant Reduction |
|
| Long -acting Barbiturates (CYP450 Induction) |
Not Studied to Result in Significant Reduction |
|
| Phenytoin*
(CYP450 Induction) |
Significantly Reduced |
Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John's Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives†
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased |
Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole† (CYP2C9, CYP2C19 and CYP3A4 Inhibition) |
Significantly Increased |
Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
| Other NNRTIs‡
(CYP3A4 Inhibition or CYP450 Induction) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness |
|
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|
The concomitant use of Alfentanil HCl Injection and CYP3A4 inhibitors can increase the plasma concentration of alfentanil, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Alfentanil HCl Injection and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Alfentanil HCl Injection is achieved After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the alfentanil plasma concentration will decrease |
|
|
If concomitant use is necessary, consider dosage reduction of Alfentanil HCl Injection until stable drug effects are achieved If a CYP3A4 inhibitor is discontinued, consider increasing the Alfentanil HCl Injection dosage until stable drug effects are achieved |
|
|
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
|
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|
|
The concomitant use of Alfentanil HCl Injection and CYP3A4 inducers can decrease the plasma concentration of alfentanil After stopping a CYP3A4 inducer, as the effects of the inducer decline, the alfentanil plasma concentration will increase |
|
|
If concomitant use is necessary, consider increasing the Alfentanil HCl Injection dosage until stable drug effects are achieved |
|
|
Rifampin, carbamazepine, phenytoin |
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Diazepam administered immediately prior to or in conjunction with high doses of Alfentanil HCl Injection may produce vasodilation and hypotension, and may result in delayed recovery. Both the magnitude and duration of central nervous system and cardiovascular effects may be enhanced when Alfentanil HCl Injection is administered in combination with other CNS depressants such as barbiturates, tranquilizers, opioids, or inhalation general anesthetics. Postoperative respiratory depression may be enhanced or prolonged by these agents. |
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Monitor patients receiving Alfentanil HCl Injection and benzodiazepines or other CNS depressants for hypotension patients and prolonged respiratory depression and sedation. In such cases of combined treatment, the dose of one or both agents should be reduced. Limited clinical experience indicates that requirements for volatile inhalation anesthetics are reduced by 30 to 50% for the first sixty (60) minutes following alfentanil induction. |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Alfentanil HCl Injection if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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Severe and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been reported rarely with alfentanil. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) |
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When Alfentanil HCl Injection is administered to patients who have received MAO inhibitors within 14 days, monitor patients for hypertension and ensure ready availability of vasodilators and beta-blockers for the treatment of hypertension as needed. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of Alfentanil HCl Injection and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Alfentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Alfentanil HCl Injection and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when Alfentanil HCl Injection is used concomitantly with anticholinergic drugs. |
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Cimetidine reduces the clearance of alfentanil, extending the duration of action. |
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Use smaller alfentanil doses for prolonged administration and monitor closely for respiratory depression and other effects of alfentanil. |
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Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Alfentanil HCl Injection. |
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Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected. |
| edema hereditary coumarin resistance hyperlipemia
|
hypothyroidism nephrotic syndrome
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| Sirolimus*
(CYP3A4 Inhibition) |
Significantly Increased | |
| Rifabutin*
(CYP3A4 Inhibition) |
Significantly Increased | |
| Efavirenz (400 mg q24h)**
(CYP3A4 Inhibition) |
Significantly Increased | |
| Efavirenz (300 mg q24h)**
(CYP3A4 Inhibition) |
Slight Increase in AUCτ | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ |
Cmax and AUCτ |
| Low-dose Ritonavir (100 mg q12h)** |
Slight Decrease in Ritonavir Cmax
and AUCτ |
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied Drug Plasma Exposure Likely to be Increased |
for QT prolongation and rare occurrence of |
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied Drug Plasma Exposure Likely to be Increased |
|
| Cyclosporine*
(CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax |
When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone***
(CYP3A4 Inhibition) |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) | Increased | Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ |
| Oxycodone (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate- associated adverse events may be necessary [ |
| NSAIDs**** including. ibuprofen and diclofenac (CYP2C9 Inhibition) |
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ |
| Tacrolimus*
(CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin*
(CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin*
(CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased |
Monitor PT or other suitable anti- coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole*
(CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one- half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
Significant Effects on Indinavir Exposure |
No dosage adjustment for indinavir when coadministered with voriconazole |
| Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors |
|
| Other NNRTIs*****
(CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied Drug Plasma Exposure Likely to be Increased |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied Drug Plasma Exposure Likely to be Increased |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
| Everolimus | Not Studied Drug Plasma Exposure Likely to be Increased |
Concomitant administration of voriconazole and everolimus is not recommended. |
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Norepinephrine Dopamine |
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| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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Celecoxib capsules have no effect on methotrexate pharmacokinetics. |
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NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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Hepatitis C protease inhibitor (boceprevir) |
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| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin | Monitor phenytoin level ( |
| Methotrexate | Monitor for methotrexate toxicity ( |
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine | Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( |
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Efavirenz (300 mg q24h) (CYP450 Induction) |
Slight Decrease in AUCτ |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
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(CYP2C9, CYP2C19 and CYP3A4 Inhibition) |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
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| Multivalent cation-containing products including : antacids, sucralfate, multivitamins | Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablets at least 4 hours before or 8 hours after these products. ( |
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. ( |
| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. |
| Antidiabetic agents | Carefully monitor blood glucose. ( |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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| a Total estrogens is the sum of conjugated and unconjugated estrogen. | ||||||
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| Estradiol | 0.037
± 0.048 |
12.7
± 9.1 |
0.676
± 0.737 |
0.030
± 0.032 |
17.32
± 1.21 |
0.561
± 0.572 |
| Estrone
Total a |
3.68
± 1.55 |
10.6
± 6.8 |
61.3
± 26.36 |
4.93
± 2.07 |
7.5
± 3.8 |
85.9
± 41.2 |
| Equilin
Total a |
2.27
± 0.95 |
6.0
± 4.0 |
28.8
± 13.0 |
3.22
± 1.13 |
5.3
± 2.6 |
38.1
± 20.2 |
|
(Mechanism of Interaction by the Drug) |
(Cmax and AUCτ after 200 mg q12h) |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 inducer; P-gp inducer) |
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containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
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(CYP3A4 Inhibition) |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
| *Change relative to reference |
|||||
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose Recommendation |
||
| Coadministered Drug |
Risperidone |
AUC |
Cmax
|
||
| Enzyme (CYP2D6) inhibitors |
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|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day |
4 mg/day |
1.6 |
- |
||
| 40 mg/day |
4 mg/day |
1.8 |
- |
||
| Enzyme (CYP3A/ PgP inducers) Inducers |
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|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) inhibitors |
|
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|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not Needed |
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
|
| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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anti-platelet therapy |
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(3,4-dihydro-cilostazol) |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
| (Mechanism of Interaction by the Drug) |
(Cmax and AUCτ after 200 mg q12h) |
|
| (CYP450 Induction) |
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| (CYP450 Induction) |
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| |
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| |
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| (CYP450 Induction) |
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| (CYP450 Induction) |
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| (CYP450 Induction) |
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| (CYP450 inducer; P-gp inducer) |
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| containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
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| (CYP3A4 Inhibition) |
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| Concomitant Drug Class:
Drug Name |
Effect on Concentration of Raltegravir | Clinical Comment |
|---|---|---|
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| aluminum and/or magnesium-containing antacids | ↓ | Coadministration or staggered administration of aluminum and/or magnesium hydroxide-containing antacids and ISENTRESS is not recommended. |
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| rifampin | ↓ | The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age
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| * Results based on ** Results based on *** Non-Nucleoside Reverse Transcriptase Inhibitors |
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| Rifampin* and Rifabutin* (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (400 mg q24h)** (CYP450 Induction) Efavirenz (300 mg q24h)** (CYP450 Induction) |
Significantly Reduced Slight Decrease in AUCτ |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h)** (CYP450 Induction) Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction) |
Significantly Reduced Reduced |
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin* (CYP450 Induction) |
Significantly Reduced |
Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John’s Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased |
Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) |
Significantly Increased |
Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
| Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly | |
|---|---|
| Digoxin Enalapril Iron Metoprolol Warfarin |
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| Ciprofloxacin | Take at least 2 hours before or 6 hours after sevelamer |
| Mycophenolate mofetil | Take at least 2 hours before sevelamer |
| |
|
|
| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) | The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) | The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs | Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. | Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines(e.g., lorazepam) | The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
| albuterol, | lomefloxacin |
| systemic and inhaled | mebendazole |
| amoxicillin | medroxyprogesterone |
| ampicillin, | methylprednisolone |
| with or without sulbactam | metronidazole |
| atenolol | metoprolol |
| azithromycin | nadolol |
| caffeine, | nifedipine |
| dietary ingestion | nizatidine |
| cefactor | norfloxacin |
| co-trimoxazole | ofloxacin |
| (trimethoprim and | omeprazole |
| sulfamethoxazole) | prednisone, prednisolone |
| diltiazem | ranitidine |
| dirithromycin | rifabutin |
| enflurane | roxithromycin |
| famotidine | sorbitol |
| felodipine | (purgative doses do not |
| finasteride | inhibit theophylline |
| hydrocortisone | absorption) |
| isoflurane | sucralfate |
| isoniazid | terbutaline, systemic |
| isradipine | terfenadine |
| influenza vaccine | tetracycline |
| ketoconazole | tocainide |
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|---|---|
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| Known CYP2D6 Poor Metabolizers |
Administer half of usual dose |
| KnownCYP2D6Poor Metabolizersand strongCYP3A4 inhibitors |
Administer a quarter of usualdose |
| StrongCYP2D6 or CYP3A4inhibitors |
Administerhalf of usual dose |
| StrongCYP2D6andCYP3A4 inhibitors |
Administer a quarter of usualdose |
| StrongCYP3A4inducers |
Double usual doseover 1 to 2 weeks |
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| Zidovudine | ↓ Ganciclovir ↑ Zidovudine |
Zidovudine and Valganciclovir each have the potential to cause neutropenia and anemia |
| Probenecid | ↑ Ganciclovir | Patients taking probenecid and Valganciclovir should be monitored for evidence of ganciclovir toxicity |
| Mycophenolate Mofetil (MMF) |
↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) |
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase |
| Didanosine | ↓ Ganciclovir ↑ Didanosine |
Patients should be closely monitored for didanosine toxicity |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
| * Change relative to reference |
|||||
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone Ratio*) |
Risperidone Dose Recommendation |
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| Coadministered Drug |
Risperidone |
AUC |
Cmax
|
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| Enzyme (CYP2D6) Inhibitors |
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| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. Do not exceed 8 mg/day |
| |
20 mg/day |
4 mg/day |
1.6 |
- |
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| |
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) Inducers |
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| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors |
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| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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Drug Name |
on Paroxetine |
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| Phenobarbital
|
Decreased paroxetine exposure
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Phenytoin |
Decreased paroxetine exposure
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Fosamprenavir/ Ritonavir |
Decreased plasma concentration
of paroxetine |
No dose adjustment for BRISDELLE.
Monitor clinical effect of BRISDELLE. |
| Cimetidine | Increased plasma concentration
of paroxetine |
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| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) | Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate |
| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated | Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs |
| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) | To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine | Use with caution (transient elevations in serum creatinine) | Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) | The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels | Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin |
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil | Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine | Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution | Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
| Reduced clearance resulting in elevated levels and prolongation of serum half-life | ||
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| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) | Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation- containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Potentiation of ciprofloxacin toxicity may occur. | ||
| Probenecid | Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) | |
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| Known CYP2D6 Poor Metabolizers
|
Administer half of usual dose
|
| KnownCYP2D6Poor Metabolizersand strongCYP3A4 inhibitors
|
Administer a quarter of usualdose
|
| StrongCYP2D6 or CYP3A4inhibitors
|
Administerhalf of usual dose
|
| StrongCYP2D6andCYP3A4 inhibitors
|
Administer a quarter of usualdose
|
| StrongCYP3A4inducers
|
Double usual doseover 1 to 2 weeks
|
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
|
| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide | ↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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| Antiarrhythmics: |
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| Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide |
Not Recommended |
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
| Digoxin | Use With Caution |
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| Oral Anticoagulants: |
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| Warfarin | Use With Caution |
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| Antiepileptics: |
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| Carbamazepine | Use With Caution |
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| Antifungals: |
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Use With Caution |
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| Fluconazole | No Dose Adjustment |
|
| Anti-Gout Agents: |
||
| Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function) |
Contraindicated Use With Caution |
|
| Antipsychotics: |
||
| Pimozide | Contraindicated |
|
| Quetiapine |
|
|
| Antispasmodics: |
||
| Tolterodine (patients deficient in CYP2D6 activity) | Use With Caution |
|
| Antivirals: |
||
| Atazanavir | Use With Caution |
|
| Saquinavir (in patients with decreased renal function) |
|
|
| Ritonavir Etravirine |
|
|
| Maraviroc |
|
|
| Boceprevir (in patients with normal renal function) Didanosine |
No Dose Adjustment |
|
| Zidovudine |
The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated. |
|
| Calcium Channel Blockers: |
||
| Verapamil | Use With Caution |
|
| Amlodipine Diltiazem |
|
|
| Nifedipine |
|
|
| Ergot Alkaloids: |
||
| Ergotamine Dihydroergotamine |
Contraindicated |
|
| Gastroprokinetic Agents: |
||
| Cisapride | Contraindicated |
|
| HMG-CoA Reductase Inhibitors: |
||
| Lovastatin Simvastatin |
Contraindicated |
|
| Atorvastatin Pravastatin |
Use With Caution | |
| Fluvastatin |
No Dose Adjustment |
|
| Hypoglycemic Agents: |
||
| Nateglinide Pioglitazone Repaglinide Rosiglitazone |
Use With Caution |
|
| Insulin |
|
|
| Immunosuppressants: |
||
| Cyclosporine | Use With Caution |
|
| Tacrolimus |
|
|
| Phosphodiesterase inhibitors: |
||
| Sildenafil Tadalafil Vardenafil |
Use With Caution |
|
| Proton Pump Inhibitors: |
||
| Omeprazole | No Dose Adjustment |
|
| Xanthine Derivatives: |
||
| Theophylline | Use With Caution |
|
| Triazolobenzodiazepines and Other Related Benzodiazepines: |
||
| Midazolam | Use With Caution |
|
| Alprazolam Triazolam |
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
|
| Temazepam Nitrazepam Lorazepam |
No Dose Adjustment |
|
| Cytochrome P450 Inducers: |
||
|
|
Use With Caution |
|
| Other Drugs Metabolized by CYP3A: |
||
| Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution | There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. |
| Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: |
||
| Hexobarbital Phenytoin Valproate |
Use With Caution | There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. |
|
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| Antifungals: |
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|
|
Use With Caution | Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also |
| Antivirals: |
||
|
|
Use With Caution |
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to |
|
|
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. |
|
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|
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|
|
|
| Saquinavir (in patients with normal renal function) | No Dose Adjustment | |
| Ritonavir (in patients with normal renal function) |
||
| Proton Pump Inhibitors: |
||
|
|
Use With Caution |
|
| Miscellaneous Cytochrome P450 Inducers: |
||
| Efavirenz Nevirapine Rifampicin Rifapentine |
Use With Caution | Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
|
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|
|---|---|---|
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|
|
|
|
| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
|
NC or 25% increase
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
|
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|
Hepatitis C protease inhibitor (boceprevir) |
|
| AED Coadministered | Dose of AED
(mg/day) |
Oxcarbazepine Tablets Dose
(mg/day) |
Influence of Oxcarbazepine Tablets on AED Concentration
(Mean Change, 90% Confidence Interval) |
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc
|
40% decrease
[CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase
[CI: 2% increase, 24% increase] |
25% decrease
[CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800
>1200-2400 |
nc
[CI: 12% increase, 60% increase] |
30% decrease
[CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc
|
18% decrease
[CI: 13% decrease, 40% decrease] |
| Interacting Drug | Interaction |
|---|---|
| Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). | QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use ( |
| Other antimalarials (e.g., halofantrine, mefloquine). | ECG abnormalities including QT prolongation. Avoid concomitant use ( |
| CYP3A4 inducers or inhibitors | Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( |
| CYP3A4 and CYP2D6 substrates | Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( |
| Digoxin | Increased digoxin plasma concentration ( |
| albuterol, systemic and inhaled | lomefloxacin |
| amoxicillin | mebendazole |
| ampicillin, with or without sulbactam | medroxyprogesterone |
| atenolol | methylprednisolone |
| azithromycin | metronidazole |
| caffeine, dietary ingestion | metoprolol |
| cefaclor | nadolol |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | nifedipine |
| diltiazem | nizatidine |
| dirithromycin | norfloxacin |
| enflurane | ofloxacin |
| famotidine | omeprazole |
| felodipine | prednisone, prednisolone |
| finasteride | ranitidine |
| hydrocortisone | rifabutin |
| isoflurane | roxithromycin |
| isoniazid | sorbitol (purgative doses do not inhibit theophylline absorption) |
| isradipine | sucralfate |
| influenza vaccine | terbutaline, systemic |
| ketoconazole | terfenadine |
| tetracycline | |
| tocainide | |
| * Refer to | |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
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|
See prescribing information for voriconazole. |
|
|
|
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia |
| Uricosuric Agents | Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
|
|
|
|
|
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. | |
| a Total estrogens is the sum of conjugated and unconjugated estrogen. | ||||||
|
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|||||
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|
| Estradiol | 0.037 ± 0.048 |
12.7 ± 9.1 |
0.676 ± 0.737 |
0.030 ± 0.032 |
17.32 ± 1.21 |
0.561 ± 0.572 |
| Estrone Total a |
3.68 ± 1.55 |
10.6 ± 6.8 |
61.3 ± 26.36 |
4.93 ± 2.07 |
7.5 ± 3.8 |
85.9 ± 41.2 |
| Equilin Total a |
2.27 ± 0.95 |
6.0 ± 4.0 |
28.8 ± 13.0 |
3.22 ± 1.13 |
5.3 ± 2.6 |
38.1 ± 20.2 |
|
|
|||||
| Coadministered Drug
|
Dosing Schedule
|
|
Effect on Active
Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose
Recommendation |
|
|
Coadministered Drug
|
Risperidone
|
AUC
|
C
m
a
x
|
|
| Enzyme (CYP2D6)
Inhibitors |
|
|
|
|
|
| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice
daily |
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day
|
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
-
|
Re-evaluate dosing.
|
|
|
20 mg/day
|
4 mg/day
|
1.6
|
-
|
Do not exceed 8 mg/day
|
|
|
40 mg/day
|
4 mg/day
|
1.8
|
-
|
|
| Enzyme (CYP3A/
PgP inducers) |
|
|
|
|
|
| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards.
Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)
Inhibitors |
|
|
|
|
|
| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not
needed |
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not
needed |
| Erythromycin
|
500 mg four times
daily |
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not
needed |
| Other Drugs
|
|
|
|
|
|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not
needed |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (
|
|
|
|
|
|
|
Avoid atorvastatin
|
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily
|
| HIV protease inhibitor (nelfinavir)
Hepatitis C Protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
|
|
The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
|
|
|
|
|
|
|
|
|
Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death |
|
|
Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. |
|
|
|
|
|
Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted |
|
|
A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration. |
|
|
|
|
|
Potential for increased exposure of digoxin |
|
|
Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. |
|
|
|
|
|
Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity. |
|
|
Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. |
|
|
|
|
|
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. |
|
|
See See |
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| |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
|
|
|
|
|
|
||
|
|
||
| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine. |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir. |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir. |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – antagonist: maraviroc | ↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
|
|
||
| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine vinblastine |
↑ anticancer agents | Concentrations of vincristine or vinblastine may be increased when co-administered with lopinavir/ritonavir (KALETRA) resulting in the potential for increased adverse events usually associated with these anticancer agents. Consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when lopinavir/ritonavir ( KALETRA) is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered:
No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone. |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. It is recommended not to exceed the following doses:
|
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA. |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Narcotic Analgesic: methadone* |
↓ methadone | Dosage of methadone may need to be increased when co-administered with KALETRA. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| a Total estrogens is the sum of conjugated and unconjugated estrogen. | ||||||
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| Estradiol | 0.037 ± 0.048 |
12.7 ± 9.1 |
0.676 ± 0.737 |
0.030 ± 0.032 |
17.32 ± 1.21 |
0.561 ± 0.572 |
| Estrone Total a |
3.68 ± 1.55 |
10.6 ± 6.8 |
61.3 ± 26.36 |
4.93 ± 2.07 |
7.5 ± 3.8 |
85.9 ± 41.2 |
| Equilin Total a |
2.27 ± 0.95 |
6.0 ± 4.0 |
28.8 ± 13.0 |
3.22 ± 1.13 |
5.3 ± 2.6 |
38.1 ± 20.2 |
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| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
| AED Coadministered | AED Concentration | Felbamate Concentration |
| Phenytoin | ↑ | ↓ |
| Valproate | ↑ | ↔** |
| Carbamazepine (CBZ)*CBZ epoxide | ↓↑ | ↓ |
| Phenobarbital | ↑ | ↓ |
| *Not significant but an active metabolie of carbamazepine. **No significant effect. | ||
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| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio
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Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) |
Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy. |
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P-gp substrate; rhabdomyolysis has been reported |
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| Concomitant Drug
|
Effect on Concentration of
Lamotrigine or Concomitant Drug |
Clinical Comment
|
| Estrogen-containing oral
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine
↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide
|
↓ lamotrigine
? carbamazepine epoxide |
Addition of carbamazepine decreases
lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 50%.
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| Atazanavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine AUC approximately 32%.
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| Phenobarbital/Primidone
|
↓ lamotrigine
|
Decreased lamotrigine concentration
approximately 40%. |
| Phenytoin
|
↓ lamotrigine
|
Decreased lamotrigine concentration
approximately 40%. |
| Rifampin
|
↓ lamotrigine
|
Decreased lamotrigine AUC
approximately 40%. |
| Valproate
|
↑ lamotrigine
? valproate |
Increased lamotrigine concentrations
slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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Norepinephrine Dopamine |
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Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg). |
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Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Celecoxib is not a substitute for low dose aspirin for cardiovascular protection. |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of celecoxib and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
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During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics. |
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During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ |
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Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)]. |
| AED Coadministered | Dose of AED (mg/day) |
Oxcarbazepine Tablets Dose (mg/day) |
Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval) |
Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc |
40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc |
18% decrease [CI: 13% decrease, 40% decrease] |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Saquinavir or Concomitant Drug | Clinical Comment |
|---|---|---|
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|
Delavirdine |
↑ Saquinavir Effect on delavirdine is not well established |
Appropriate doses of the combination with respect to safety and efficacy have not been established. Coadministration is not recommended. Liver function should be monitored frequently if this combination is prescribed. |
|
Efavirenz nevirapine |
↓ Saquinavir ↔ Efavirenz |
Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Coadministration is not recommended. |
|
Indinavir |
↑ Saquinavir ↑ Indinavir |
Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Coadministration is not recommended. Increased concentrations of indinavir may result in nephrolithiasis. For further details see complete prescribing information for Crixivan® (indinavir). |
|
Lopinavir/ritonavir |
↔ Saquinavir ↔ Lopinavir ↓ Ritonavir |
Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following INVIRASE/ritonavir 1000/100 mg. The recommended dose for this combination is INVIRASE 1000 mg plus lopinavir/ritonavir 400/100 mg bid. Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE |
|
Nelfinavir |
↑ Saquinavir |
Combining saquinavir/ritonavir with nelfinavir is not recommended. |
|
Tipranavir/ritonavir |
↓ Saquinavir |
Combining saquinavir with tipranavir/ritonavir is not recommended. |
|
Maraviroc |
↑ Maraviroc | Maraviroc dose should be 150 mg twice daily when coadministered with INVIRASE/ritonavir. For further details see complete prescribing information for Selzentry® (maraviroc). |
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| Ibutilide Sotalol |
Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir |
|
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Warfarin |
↑ Warfarin | Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. |
|
Carbamazepine |
↓ Saquinavir Effect on carbamazepine, phenobarbital, and phenytoin is not well established |
Saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. Coadministration is not recommended. |
|
Colchicine |
↑ Colchicine |
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Patients with renal or hepatic impairment should not be given colchicine with INVIRASE/ritonavir. |
| Streptogramin antibiotics (quinupristin/dalfopristin |
Streptogramin antibiotics such as quinupristin/dalfopristin inhibit CYP3A4; saquinavir concentrations may be increased | Monitoring for saquinavir toxicity is recommended. Use with caution due to possible cardiac arrhythmias. |
| Fusidic acid | ↑ Saquinavir ↑ Fusidic Acid ↑ Ritonavir |
Concomitant use of fusidic acid and INVIRASE/ritonavir is not recommended due to potential for increased mutual toxicities. The interaction between INVIRASE/ritonavir and fusidic acid has not been formally evaluated. Co-administration of fusidic acid and INVIRASE/ritonavir can cause increased plasma concentrations of fusidic acid, saquinavir and ritonavir. |
|
Ketoconazole itraconazole |
↔ Saquinavir ↔ Ritonavir ↑ Ketoconazole |
When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentrations of ketoconazole are increased (see |
|
Rifabutin |
↔ Saquinavir ↑ Rifabutin ↔ Ritonavir |
No dose adjustment of INVIRASE/ritonavir (1000/100 mg bid) is required if INVIRASE/ritonavir is administered in combination with rifabutin. Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events including neutropenia and liver enzyme levels is warranted in patients receiving the combination. Consider monitoring rifabutin concentrations to ensure adequate exposure. |
|
Quetiapine |
↑ Quetiapine |
Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
|
Alprazolam, clorazepate, diazepam, flurazepam |
↑ Benzodiazepines | Clinical significance is unknown. Careful monitoring of patients for benzodiazepine effects is warranted; a decrease in benzodiazepine dose may be needed. |
|
Intravenously administered Midazolam |
↑ Midazolam | If INVIRASE/ritonavir is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered. |
|
Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine |
↑ Calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
|
Dexamethasone |
↓ Saquinavir |
INVIRASE/ritonavir may be less effective due to decreased saquinavir plasma concentrations. Coadministration is not recommended. |
|
|
↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir. |
Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir. |
|
Bosentan |
↑ Bosentan |
In patients who have been receiving INVIRASE/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of INVIRASE/ritonavir. After at least 10 days following the initiation of INVIRASE/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
Salmeterol |
↑ Salmeterol | Concurrent administration of salmeterol with INVIRASE/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
|
Fluticasone Budesonide |
↑ Fluticasone | Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Several cases of Cushing's disease associated with this interaction have been reported in the literature. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. If the combination is nevertheless considered necessary, a dose reduction of fluticasone propionate with close monitoring of local and systemic effects is recommended. A switch to a corticosteroid which is not a substrate for CYP3A (e.g., beclomethasone) should be considered. In case of withdrawal of corticosteroids, progressive dose reduction may have to be performed over a longer period. |
|
Atorvastatin |
↑ Atorvastatin |
Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day. Patients should be carefully monitored for signs and symptoms of myopathy (e.g., muscle weakness, muscle pain, rising creatine kinase). |
|
Cyclosporine, rapamycin |
↑ Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir. |
|
Methadone |
↓ Methadone | Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir. Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir |
|
Ethinyl estradiol |
↓ Ethinyl estradiol | Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered. |
|
Sildenafil |
↑ Sildenafil ↔ Saquinavir ↑ Vardenafil ↑ Tadalafil Only the combination of sildenafil with saquinavir soft gelatin capsules has been studied at doses used for treatment of erectile dysfunction. |
May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
In patients receiving INVIRASE/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of Adcirca during the initiation of INVIRASE/ritonavir. Stop Adcirca at least 24 hours prior to starting INVIRASE/ritonavir. After at least one week following the initiation of INVIRASE/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. |
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|
↑ Tricyclics | Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir. |
|
Nefazodone |
↑ Saquinavir | Monitoring for saquinavir toxicity is recommended. |
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↑ Saquinavir | When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation. |
|
St. John's wort |
↓ Saquinavir | Herbal products containing St. John's wort should not be used concomitantly with INVIRASE/ritonavir because coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors. |
|
Fentanyl Alfentanil |
↑ Fentanyl ↑ Alfentanil |
Coadministration with these drugs may accentuate the side effects reported with use of fentanyl or alfentanil including respiratory depression, apnea and bradycardia. |
|
Intravenously administered Vincamine |
↑ Vincamine | Monitoring for vincamine toxicity is recommended. Use with caution due to potential cardiac arrhythmias. |
| Garlic Capsules |
↓ Saquinavir | Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations. |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
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Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
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| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
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| Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
| blood dyscrasias - see cancer collagen vascular disease congestive heart failure |
diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice |
hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency |
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| Tizanidine |
Contraindicated |
Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline |
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. |
| Drugs Known to Prolong QT Interval |
Avoid Use |
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs |
Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin |
Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine |
Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs |
Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate |
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole |
Use with caution |
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin |
| Clozapine |
Use with caution |
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs |
Use with caution |
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing. |
| Sildenafil |
Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine |
Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
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| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Probenecid |
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
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Hepatitis C Protease inhibitor (boceprevir) |
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Sulfonylureas | Hypoglycemia potentiated. | ||
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. | ||
| Oral Anticoagulants | Increased bleeding. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. | ||
| Acidifying Agents | Increases plasma salicylate levels. | ||
| Alkanizing Agents | Decreased plasma salicylate levels. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. | ||
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. | ||
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. | ||
| The following alterations of laboratory tests have been reported during salicylate therapy: | |||
| LABORATORY TESTS | EFFECT OF SALICYLATES | ||
| Thyroid Function | Decreased PBI; increased t3 uptake. | ||
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). | ||
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. | ||
| Acetone ketone bodies | False positive FeCI3 in Gerhardt reaction; red color persists with boiling. | ||
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. | ||
| Vanilmandelic acid | False reduced values. | ||
| Uric Acid | May increase or decrease depending on dose. | ||
| Prothrombin | Decreased levels; slightly increased prothrombin time. | ||
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 50 mg (95% CI) |
|---|---|
| Supine | 9.08 (5.48, 12.68) |
| Standing |
11.62 (7.34, 15.90) |
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| Strong CYP3A4 Inhibitors | |
|---|---|
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Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided |
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Boceprevir, clarithromycin, conivaptan, grapefruit juice |
| Strong CYP3A4 Inducers | |
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Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided |
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Rifampin, phenytoin, carbamazepine, phenobarbital, rifabutin, rifapentine, and St. John’s Wort |
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| Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin,
clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol |
Contraindicated with VYTORIN |
| Verapamil, diltiazem, dronedarone | Do not exceed 10/10 mg VYTORIN daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 10/20 mg VYTORIN daily |
| Lomitapide | For patients with HoFH, do not exceed 10/20 mg VYTORIN daily
|
| Grapefruit juice | Avoid grapefruit juice |
| ↓= Decreased (induces lamotrigine glucuronidation). | ||
| ↑= Increased (inhibits lamotrigine glucuronidation). | ||
| ? = Conflicting data. | ||
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| AED Coadministered | Dose of AED (mg/day)
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Oxcarbazepine Tablets Dose (mg/day)
|
Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval) | Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc
|
40% decrease [CI:17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] | 25% decrease [CI:12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 | nc
|
30% decrease |
| >1200-2400 | up to 40% increase [CI: 12% increase, 60% increase]
|
[CI: 3% decrease, 48% decrease] | ||
| Valproic acid | 400-2800 | 600-1800 | nc
|
18% decrease [CI:13% decrease, 40% decrease] |
| * Change relative to reference |
|||||
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone Ratio*) |
Risperidone Dose Recommendation |
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| Coadministered Drug |
Risperidone |
AUC |
Cmax
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| Enzyme (CYP2D6) Inhibitors |
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| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. Do not exceed 8 mg/day |
| |
20 mg/day |
4 mg/day |
1.6 |
- |
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40 mg/day |
4 mg/day |
1.8 |
- |
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| Enzyme (CYP3A/ PgP inducers) Inducers |
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| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors |
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| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation- containing products including: antacids, sucralfate, multivitamins | Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (
|
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (
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| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. (
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| Antidiabetic agents | Carefully monitor blood glucose. (
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
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| ciprofloxacin | melphalan | azapropazon | cimetidine |
| gentamicin | colchicine | ranitidine | |
| tobramycin |
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diclofenac | |
| vancomycin | amphotericin B | naproxen |
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| trimethoprim with sulfamethoxazole | ketoconazole | sulindac | tacrolimus |
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| fibric acid derivatives (e.g.,bezafibrate, fenofibrate) |
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| methotrexate |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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|---|---|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
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| Clinical Impact | Because INVEGA SUSTENNA® has the potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA SUSTENNA® is administered with other therapeutic agents that have this potential |
| Intervention | Monitor orthostatic vital signs in patients who are vulnerable to hypotension |
| Examples | Nitrates Antihypertensive medicines: thiazide diuretics (e.g. hydrochlorothiazide); beta blockers (e.g. acebutolol); angiotensin-converting enzyme (ACE) inhibitors (e.g. lisinopril); angiotensin II receptor blockers (ARBs) (e.g. candesartan); calcium channel blockers (e.g. amlodipine); alpha-blockers (e.g. prazosin), alpha-agonists (e.g. clonidine), other diuretics (e.g. loop, K-sparing), vasodilators (e.g. hydralazine) |
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| Clinical Impact | The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone |
| Intervention | Avoid using CYP3A4 and/or P-gp inducers with INVEGA SUSTENNA® during the 1-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended release tablets |
| Examples | Carbamazepine, rifampin, St John's Wort |
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| Clinical Impact | Paliperidone may antagonize the effect of levodopa and other dopamine agonist |
| Intervention | Monitor and manage patient as clinically appropriate |
| Examples | Levodopa, bromocriptine, ropinirole and pramipexole |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 inducer; P-gp inducer) |
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containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
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(CYP3A4 Inhibition) |
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| Tizanidine | Contraindicated | Concomitant administration of tizanidine and Ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [
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| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) | Concurrent administration of Ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate.
|
| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)
|
| Oral antidiabetic drugs
|
Use with caution Glucose-lowering effect potentiated | Hypoglycemia sometimes severe has been reported when Ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when Ciprofloxacin is co-administered with oral antidiabetic drugs.
|
| Phenytoin
|
Use with caution Altered serum levels of phenytoin (increased and decreased) | To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon Ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of Ciprofloxacin with phenytoin. |
| Cyclosporine
|
Use with caution (transient elevations in serum creatinine) | Monitor renal function (in particular serum creatinine) when Ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs
|
Use with caution (Increase in anticoagulant effect) | The risk may vary with the underlying infection, age and general status of the patient so that the contribution of Ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of Ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate
|
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels | Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant Ciprofloxacin therapy is indicated. |
| Ropinirole
|
Use with caution
|
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with Ciprofloxacin
|
| Clozapine
|
Use with caution
|
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with Ciprofloxacin are advised. |
| NSAIDs
|
Use with caution
|
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil
|
Use with caution Two-fold increase in exposure | Monitor for sildenafil toxicity (
|
| Duloxetine
|
Avoid Use
Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity. |
| Caffeine/Xanthine
Derivatives |
Use with caution
Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
|
|
||
| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration
|
Decrease Ciprofloxacin absorption, resulting in lower serum and urine levels
|
| Probenecid | Use with caution (interferes with renal tubular secretion of Ciprofloxacin and increases Ciprofloxacin serum levels) | Potentiation of Ciprofloxacin toxicity may occur. |
| Interaction Drug |
|
|---|---|
| Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazole |
|
| Other drugs metabolized by CYP3A4 |
|
| Digoxin |
|
| Fosamprenavir, metoclopramide |
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|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
|
|
|
| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
These drugs may increase serum thyroxine-binding globulin (TBG) concentration. |
| Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
These drugs may decrease serum TBG concentration. |
| Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations. | |
| Salicylates (> 2 g/day) | Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%. |
| Other drugs:
Carbamazepine Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates |
These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters. |
|
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|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Clarithromycin | 500 twice daily, 7 days |
800 three times daily, 7 days | 12 | 1.19 (1.02, 1.39) |
1.47 (1.30, 1.65) |
1.97 (1.58, 2.46) n=11 |
| Efavirenz | 200 once daily, 14 days |
800 three times daily, 14 days | 20 | No significant change | No significant change | -- |
| Ethinyl Estradiol (ORTHO-NOVUM 1/35) |
35 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.02 (0.96, 1.09) |
1.22 (1.15, 1.30) |
1.37 (1.24, 1.51) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 8 days | 11 | 1.34 (1.12, 1.60) |
1.12 (1.03, 1.22) |
1.00 (0.92, 1.08) |
| Methadone |
20-60 once daily in the morning, 8 days |
800 three times daily, 8 days | 12 | 0.93 (0.84, 1.03) |
0.96 (0.86, 1.06) |
1.06 (0.94, 1.19) |
| Norethindrone (ORTHO-NOVUM 1/35) |
1 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.05 (0.95, 1.16) |
1.26 (1.20, 1.31) |
1.44 (1.32, 1.57) |
| Rifabutin •150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone |
150 once daily in the morning, 10 days 300 once daily in the morning, 10 days |
800 three times daily, 10 days 800 three times daily, 10 days |
14 10 |
1.29 (1.05, 1.59) 2.34 (1.64, 3.35) |
1.54 (1.33, 1.79) 2.73 (1.99, 3.77) |
1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9 |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 4 |
1.61 (1.13, 2.29) |
1.72 (1.20, 2.48) |
1.62 (0.93, 2.85) |
| 200 twice daily, 14 days |
800 twice daily, 14 days |
9, 5 |
1.19 (0.85, 1.66) |
1.96 (1.39, 2.76) |
4.71 (2.66, 8.33) n=9, 4 |
|
| Saquinavir | ||||||
| Hard gel formulation | 600 single dose | 800 three times daily, 2 days | 6 | 4.7 (2.7, 8.1) |
6.0 (4.0, 9.1) |
2.9 (1.7, 4.7) |
| Soft gel formulation | 800 single dose | 800 three times daily, 2 days | 6 | 6.5 (4.7, 9.1) |
7.2 (4.3, 11.9) |
5.5 (2.2, 14.1) |
| Soft gel formulation | 1200 single dose | 800 three times daily, 2 days | 6 | 4.0 (2.7, 5.9) |
4.6 (3.2, 6.7) |
5.5 (3.7, 8.3) |
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| Stavudine |
40 twice daily, 7 days |
800 three times daily, 7 days | 13 | 0.86 (0.73, 1.03) |
1.21 (1.09, 1.33) |
Not Done |
| Theophylline | 250 single dose (on Days 1 and 7) | 800 three times daily, 6 days (Days 2 to 7) | 12, 4 |
0.88 (0.76, 1.03) |
1.14 (1.04, 1.24) |
1.13 (0.86, 1.49) n=7, 3 |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Trimethoprim | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.18 (1.05, 1.32) |
1.18 (1.05, 1.33) |
1.18 (1.00, 1.39) |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Sulfamethoxazole | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.01 (0.95, 1.08) |
1.05 (1.01, 1.09) |
1.05 (0.97, 1.14) |
| Vardenafil | 10 single dose | 800 three times daily | 18 | See text below for discussion of interaction. | ||
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days | 12 | 0.89 (0.73, 1.09) |
1.17 (1.07, 1.29) |
1.51 (0.71, 3.20) n=4 |
| Zidovudine/ Lamivudine |
||||||
| Zidovudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
1.23 (0.74, 2.03) |
1.39 (1.02, 1.89) |
1.08 (0.77, 1.50) n=5, 5 |
| Zidovudine/ Lamivudine |
||||||
| Lamivudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
0.73 (0.52, 1.02) |
0.91 (0.66, 1.26) |
0.88 (0.59, 1.33) |
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Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
|
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|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
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|
|
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
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|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
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|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
|||
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|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
|||
| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| NA = Not available/reported | |||
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Concentration Increase |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol |
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20 mg simvastatin daily |
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| Drug/Drug Class (Mechanism of Interaction by the Drug) |
Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg q12h) |
Recommendations for Voriconazole Dosage Adjustment/Comments |
|---|---|---|
| Rifampin (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (400 mg q24h) (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (300 mg q24h) (CYP450 Induction) |
Slight Decrease in AUC |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
Significantly Reduced |
|
| Low-dose Ritonavir (100 mg q12h) |
Reduced | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John's Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole |
Significantly Increased | Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir |
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|
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
|
| Other NNRTIs (CYP3A4 Inhibition or CYP450 Induction) |
|
Frequent monitoring for adverse events and toxicity related to voriconazole |
| A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Careful assessment of voriconazole effectiveness |
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| Clinical Impact: | Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. | |
| Intervention: |
Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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| Clinical Impact: |
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
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| Intervention: |
Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
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| Clinical Impact: | NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. | |
| Intervention: |
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [
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| Clinical Impact: |
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [
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| Intervention: |
Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [
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| Clinical Impact: | The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. | |
| Intervention: | During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. | |
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| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. | |
| Intervention: | During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. | |
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| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). | |
| Intervention: | During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity. | |
| Intervention: | During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. | |
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| Clinical Impact: |
Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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| Intervention: | The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). | |
| Intervention: | During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. | |
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| Clinical Impact: | When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. | |
| Intervention: | During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. | |
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|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
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Hepatitis C protease inhibitor (boceprevir) |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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| Phenytoin
|
NCor25%increase
a
|
48%decrease
|
| Carbamazepine(CBZ)
|
NC
|
40%decrease
|
| CBZepoxide
b
|
NC
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NE
|
| Valproic acid
|
11%decrease
|
14%decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
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NE
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| Lamotrigine
|
NCatTPM dosesupto400 mg/day
|
13%decrease
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
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Efavirenz (300 mg q24h) (CYP3A4 Inhibition) |
Slight Increase in AUCτ |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
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(CYP3A4 Inhibition) |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
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| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
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|---|---|
| Clinical Impact | MAOI antidepressants slow amphetamine metabolism, increasing amphetamines effect on the release of norepinephrine and other monoamines from adrenergic nerve endings causing headaches and other signs of hypertensive crisis. Toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results. |
| Intervention | Do not administer ADZENYS XR-ODT during or within 14 days following the administration of MAOI [see |
| Examples | selegiline, isocarboxazid, phenelzine, tranylcypromine |
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| Clinical Impact | The concomitant use of ADZENYS XR-ODT and serotonergic drugs increases the risk of serotonin syndrome. |
| Intervention | Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during ADZENYS XR-ODT initiation or dosage increase. If serotonin syndrome occurs, discontinue ADZENYS XR-ODT and the concomitant serotonergic drug(s) [see |
| Examples | selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort |
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| Clinical Impact | Increase blood levels and potentiate the action of amphetamine. |
| Intervention | Co-administration of ADZENYS XR-ODT and gastrointestinal alkalinizing agents should be avoided. |
| Examples | Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g., acetazolamide, some thiazides). |
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| Clinical Impact | Lower blood levels and efficacy of amphetamines. |
| Intervention | Increase dose based on clinical response. |
| Examples | Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid). |
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| Clinical Impact | May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. |
| Intervention | Monitor frequently and adjust or use alternative therapy based on clinical response. |
| Examples | desipramine, protriptyline |
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| ciprofloxacin | melphalan | azapropazon | cimetidine |
| gentamicin | colchicine | ranitidine | |
| tobramycin | |
diclofenac | |
| trimethoprim | amphotericin B | naproxen | |
| with | ketoconazole | sulindac | tacrolimus |
| sulfamethoxazole | |||
| vancomycin | |
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| fibric acid derivatives | |||
| (e.g., bezafibrate, | |||
| fenofibrate) | |||
| methotrexate |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. | |
| Allopurinol | |
25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increase theophylline clearance. | 20% increase |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20 to 40% decrease |
| Sulfinpyrazone | Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% increase |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33 to 100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
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| Corticosteroids | Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism |
| Ammonium Sulfate | Increases plasma salicylate level |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
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| ↑ Indicates increase. ↓ Indicates decrease. a The dosing recommendation for coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to meal consumption differs from that of VIDEX. See the complete prescribing information for VIDEX EC. |
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| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
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| Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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| ↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
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150 mcg levonorgestrel |
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
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? carbamazepine epoxide |
May increase carbamazepine epoxide levels. |
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? valproate |
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| Concomitant Drug Name or Drug Class |
Clinical Rationale and Magnitude of Drug Interaction | Clinical Recommendation |
| Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure |
Consider dose reduction |
| Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure |
Consider dose increase |
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a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b= Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated |
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| Drug | Description |
|---|---|
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism |
| Ammonium Sulfate | Increases plasma salicylate level |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Concomitant Drug Class or Food | Noted or anticipated Outcome | Clinical Comment |
|---|---|---|
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atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) | Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy. |
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fibrates, gemfibrozil |
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digoxin |
P-gp substrate; rhabdomyolysis has been reported |
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(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
| a Total estrogens is the sum of conjugated and unconjugated estrogen. | ||||||
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| Estradiol | 0.037 ± 0.048 |
12.7 ± 9.1 |
0.676 ± 0.737 |
0.030 ± 0.032 |
17.32 ± 1.21 |
0.561 ± 0.572 |
| Estrone Total a |
3.68 ± 1.55 |
10.6 ± 6.8 |
61.3 ± 26.36 |
4.93 ± 2.07 |
7.5 ± 3.8 |
85.9 ± 41.2 |
| Equilin Total a |
2.27 ± 0.95 |
6.0 ± 4.0 |
28.8 ± 13.0 |
3.22 ± 1.13 |
5.3 ± 2.6 |
38.1 ± 20.2 |
| Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24) | ||
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(Peak plasma concentration) |
(Extent of systemic exposure) |
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
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| Delavirdine or other non-nucleoside reverse transcriptase inhibitors (NNRTIs) | Decrease in delavirdine or NNRTI levels | Contraindicated with carbamazepine |
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| Tricyclic antidepressants | Increase blood pressure and may counteract clonidine’s hypotensive effects | Monitor blood pressure and adjust as needed |
| Antihypertensive drugs | Potentiate clonidine’s hypotensive effects | Monitor blood pressure and adjust as needed |
| CNS depressants | Potentiate sedating effects | Avoid use |
| Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers) | Potentiate bradycardia and risk of AV block | Avoid use |
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Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
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| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Clarithromycin | 500 twice daily, 7 days |
800 three times daily, 7 days | 12 | 1.19 (1.02, 1.39) |
1.47 (1.30, 1.65) |
1.97 (1.58, 2.46) n=11 |
| Efavirenz | 200 once daily, 14 days |
800 three times daily, 14 days | 20 | No significant change | No significant change | -- |
| Ethinyl Estradiol (ORTHO-NOVUM 1/35) |
35 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.02 (0.96, 1.09) |
1.22 (1.15, 1.30) |
1.37 (1.24, 1.51) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 8 days | 11 | 1.34 (1.12, 1.60) |
1.12 (1.03, 1.22) |
1.00 (0.92, 1.08) |
| Methadone |
20-60 once daily in the morning, 8 days |
800 three times daily, 8 days | 12 | 0.93 (0.84, 1.03) |
0.96 (0.86, 1.06) |
1.06 (0.94, 1.19) |
| Norethindrone (ORTHO-NOVUM 1/35) |
1 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.05 (0.95, 1.16) |
1.26 (1.20, 1.31) |
1.44 (1.32, 1.57) |
| Rifabutin 150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone |
150 once daily in the morning, 10 days 300 once daily in the morning, 10 days |
800 three times daily, 10 days 800 three times daily, 10 days |
14 10 |
1.29 (1.05, 1.59) 2.34 (1.64, 3.35) |
1.54 (1.33, 1.79) 2.73 (1.99, 3.77) |
1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9 |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 4 |
1.61 (1.13, 2.29) |
1.72 (1.20, 2.48) |
1.62 (0.93, 2.85) |
| 200 twice daily, 14 days |
800 twice daily, 14 days |
9, 5 |
1.19 (0.85, 1.66) |
1.96 (1.39, 2.76) |
4.71 (2.66, 8.33) n=9, 4 |
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| Saquinavir | ||||||
| Hard gel formulation | 600 single dose | 800 three times daily, 2 days | 6 | 4.7 (2.7, 8.1) |
6.0 (4.0, 9.1) |
2.9 (1.7, 4.7) |
| Soft gel formulation | 800 single dose | 800 three times daily, 2 days | 6 | 6.5 (4.7, 9.1) |
7.2 (4.3, 11.9) |
5.5 (2.2, 14.1) |
| Soft gel formulation | 1200 single dose | 800 three times daily, 2 days | 6 | 4.0 (2.7, 5.9) |
4.6 (3.2, 6.7) |
5.5 (3.7, 8.3) |
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| Stavudine |
40 twice daily, 7 days |
800 three times daily, 7 days | 13 | 0.86 (0.73, 1.03) |
1.21 (1.09, 1.33) |
Not Done |
| Theophylline | 250 single dose (on Days 1 and 7) | 800 three times daily, 6 days (Days 2 to 7) | 12, 4 |
0.88 (0.76, 1.03) |
1.14 (1.04, 1.24) |
1.13 (0.86, 1.49) n=7, 3 |
| Trimethoprim/ Sulfamethoxazole |
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| Trimethoprim | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.18 (1.05, 1.32) |
1.18 (1.05, 1.33) |
1.18 (1.00, 1.39) |
| Trimethoprim/ Sulfamethoxazole |
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| Sulfamethoxazole | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.01 (0.95, 1.08) |
1.05 (1.01, 1.09) |
1.05 (0.97, 1.14) |
| Vardenafil | 10 single dose | 800 three times daily | 18 | See text below for discussion of interaction. | ||
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days | 12 | 0.89 (0.73, 1.09) |
1.17 (1.07, 1.29) |
1.51 (0.71, 3.20) n=4 |
| Zidovudine/ Lamivudine |
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| Zidovudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
1.23 (0.74, 2.03) |
1.39 (1.02, 1.89) |
1.08 (0.77, 1.50) n=5, 5 |
| Zidovudine/ Lamivudine |
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| Lamivudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
0.73 (0.52, 1.02) |
0.91 (0.66, 1.26) |
0.88 (0.59, 1.33) |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
| AED Co-administered | AED Concentration | Topiramate Concentration |
| Phenytoin |
NC or 25% increasea | 48% decrease |
| Carbamazepine (CBZ) | NC |
40% decrease |
| CBZ epoxideb | NC |
NE |
| Valproic acid |
11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone |
NC | NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day | 13% decrease |
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Naproxen may decrease platelet aggregation and prolong bleeding time. |
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This effect should be kept in mind when bleeding times are determined. |
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The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. |
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Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. |
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Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). |
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This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined. |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with ezetimibe and simvastatin tablets |
| Verapamil, diltiazem, dronedarone | Do not exceed ezetimibe and simvastatin tablets, 10 mg/10 mg daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed ezetimibe and simvastatin tablets, 10 mg/20 mg daily |
| Lomitapide | For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets1 |
| Grapefruit juice | Avoid grapefruit juice |
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| Clinical Impact | Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. |
| Intervention | Do not administer ADDERALL XR concomitantly or within 14 days after discontinuing MAOI |
| Examples | selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
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| Clinical Impact | The concomitant use of ADDERALL XR and serotonergic drugs increases the risk of serotonin syndrome. |
| Intervention | Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during ADDERALL XR initiation or dosage increase. If serotonin syndrome occurs, discontinue ADDERALL XR and the concomitant serotonergic drug(s) |
| Examples | selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort |
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| Clinical Impact | The concomitant use of ADDERALL XR and CYP2D6 inhibitors may increase the exposure of ADDERALL XR compared to the use of the drug alone and increase the risk of serotonin syndrome. |
| Intervention | Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during ADDERALL XR initiation and after a dosage increase. If serotonin syndrome occurs, discontinue ADDERALL XR and the CYP2D6 inhibitor |
| Examples | paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir |
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| Clinical Impact | Increase blood levels and potentiate the action of amphetamine. |
| Intervention | Co-administration of ADDERALL XR and gastrointestinal or urinary alkalinizing agents should be avoided. |
| Examples | Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g. acetazolamide, some thiazides). |
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| Clinical Impact | Lower blood levels and efficacy of amphetamines. |
| Intervention | Increase dose based on clinical response. |
| Examples | Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid). Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts). |
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| Clinical Impact | May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. |
| Intervention | Monitor frequently and adjust or use alternative therapy based on clinical response. |
| Examples | desipramine, protriptyline |
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| Clinical Impact | Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone. |
| Intervention | Monitor patients for changes in clinical effect and adjust therapy based on clinical response. |
| Examples | omeprazole |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Concomitant Drug Name or Drug Class | Clinical Rationale | Clinical Recommendation |
|---|---|---|
| Acidifying and Alkalinizing Agents | Ascorbic acid and other agents that acidify urine increase urinary excretion and decrease the half-life of amphetamine. Sodium bicarbonate and other agents that alkalinize urine decrease urinary excretion and extend the half-life of amphetamine. | Adjust the dose accordingly |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| Interacting Agents | Prescribing Recommendations |
| Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
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Monitor patients with concomitant use of MOBIC with anticoagulants
(e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin
reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake
inhibitors (SNRIs) for signs of bleeding [
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Controlled clinical studies showed that the concomitant
use of NSAIDs and analgesic doses of aspirin does not produce any
greater therapeutic effect than the use of NSAIDs alone. In a clinical
study, the concomitant use of an NSAID and aspirin was associated
with a significantly increased incidence of GI adverse reactions as
compared to use of the NSAID alone [
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Concomitant
use of MOBIC and low dose aspirin or analgesic doses of aspirin is
not generally recommended because of the increased risk of bleeding
[
MOBIC is not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of MOBIC with diuretics, observe
patients for signs of worsening renal function, in addition to assuring
diuretic efficacy including antihypertensive effects [
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NSAIDs have produced elevations in plasma lithium levels
and reductions in renal lithium clearance. The mean minimum lithium
concentration increased 15%, and the renal clearance decreased by
approximately 20%. This effect has been attributed to NSAID inhibition
of renal prostaglandin synthesis [
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During concomitant use of MOBIC and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of MOBIC and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of MOBIC and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of MOBIC and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates
(e.g., diflunisal, salsalate) increases the risk of GI toxicity, with
little or no increase in efficacy [
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of MOBIC and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of MOBIC and pemetrexed, in patients
with renal impairment whose creatinine clearance ranges from 45 to
79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone |
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Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis |
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During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
|
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During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
| |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases theophylline clearance at allopurinol doses ≥600 mg/day. | 25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects. | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20 to 40% decrease |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33 to 100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
| *Refer to |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily* |
| Grapefruit juice | Avoid grapefruit juice |
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|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites. |
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| Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. | |
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| Beta-adrenergic antagonists
(e.g., Propranolol > 160 mg/day) |
In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state. |
| Glucocorticoids
(e.g., Dexamethasone |
Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above). |
| Other drugs:
Amiodarone |
Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide
|
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
|
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
|
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
|
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
Drug Name |
Other Drugs |
|
| Thioridazine
|
Increased plasma concentrations of thioridazine
Potential QTc prolongation |
Concomitant use of thioridazine and BRISDELLE is
contraindicated. |
| Pimozide
|
Increased plasma concentrations
of pimozide. Potential QTc prolongation |
Concomitant use of pimozide and BRISDELLE is
contraindicated. |
| Tamoxifen
|
Reduced plasma concentrations
of active tamoxifen metabolite |
Consider avoiding concomitant use of tamoxifen
and BRISDELLE. |
|
Tricyclic Antidepressant (TCA) (e.g., Desipramine) |
Increased plasma concentrations
and elimination half-life |
Plasma TCA concentrations may need to be
monitored and the dose of TCA may need to be reduced if a TCA is co-administered with BRISDELLE. Monitor tolerability. |
| Risperidone
|
Increased plasma concentrations
of risperidone |
A lower dosage of risperidone may be necessary
(see the Full Prescribing Information for risperidone). Monitor tolerability. |
| Atomoxetine
|
Increased exposure of
atomoxetine |
A lower dosage of atomoxetine may be necessary
(see Full Prescribing Information for atomoxetine). Monitor tolerability. |
| Drugs Highly Bound
to Plasma Protein (e.g., Warfarin) |
Increased free plasma
concentrations |
The dosage of warfarin may need to be reduced.
Monitor tolerability and the International Normalized Ratio. |
| Digoxin
|
Decreased plasma concentrations
of digoxin |
Dosage of digoxin may need to be increased.
Monitor digoxin concentrations and clinical effect. |
| Theophylline
|
Increased plasma concentrations
of theophylline |
Dosage of theophylline may need to be decreased.
Monitor theophylline concentrations and tolerability. |
| Drug | Description of Interaction |
|---|---|
| Tolbutamide; Sulfonylureas | Hypoglycemia potentiated |
| Methotrexate | Decrease tubular reabsorption; clinical toxicity from methotrexate can result |
| Oral Anticoagulants | Increased bleeding |
| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
|
NC or 25% increase
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
|
|
|
|
| Theophylline |
Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents |
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin |
Monitor phenytoin level ( |
| Methotrexate |
Monitor for methotrexate toxicity ( |
| Cyclosporine |
May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( |
|
|
|
|
|
|
|
Glucocorticoids Octreotide |
|
|
|
|
|
|
|
|
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
|
|
|
|
|
Iodide (including iodine-containing Radiographic contrast agents) |
|
|
|
|
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
|
|
|
|
|
|
|
|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
|
|
|
|
|
|
|
|
Hydantoins Phenobarbital Rifampin |
|
|
|
|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
|
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
|
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
|
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
|
|
|
|
|
- Interferon-α - Interleukin-2 |
|
|
- Somatrem - Somatropin |
|
|
|
|
|
- (e.g., Theophylline) |
|
|
|
|
|
|
|
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
|
|
|
|
|
|
| nafcillin | carbamazepine | bosentan | St. John’s Wort |
| rifampin | oxcarbazepine | octreotide | |
| phenobarbital | orlistat | ||
| phenytoin | sulfinpyrazone | ||
| terbinafine | |||
| ticlopidine | |||
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) | Do not exceed 40 mg atorvastatin daily |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
|
|
|
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
|
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding |
|
|
|
|
|
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone |
|
|
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
|
|
|
|
|
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
|
|
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function |
|
|
|
|
|
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
|
|
During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects |
|
|
|
|
|
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis |
|
|
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. |
|
|
|
|
|
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
|
|
During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
|
|
|
|
|
Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. |
|
|
During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
|
|
|
|
|
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy |
|
|
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
|
|
|
|
|
Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
|
|
During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
|
|
|
|
|
Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. |
|
|
Dose reductions and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs. |
|
|
|
|
|
Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones |
|
|
Dose increases and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs. |
|
|
|
|
|
Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. |
|
|
Dose adjustment and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs. |
|
|
|
|
|
beta-blockers, clonidine, guanethidine, and reserpine |
|
|
Increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs. |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
|
| Phenytoin
|
NCor25%increase
a
|
48%decrease
|
| Carbamazepine(CBZ)
|
NC
|
40%decrease
|
| CBZepoxide
b
|
NC
|
NE
|
| Valproic acid
|
11%decrease
|
14%decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NCatTPM dosesupto400 mg/day
|
13%decrease
|
|
|
|
|
| Tricyclic antidepressants | Increase blood pressure and may counteract clonidine’s hypotensive effects | Monitor blood pressure and adjust as needed |
| Antihypertensive drugs | Potentiate clonidine’s hypotensive effects | Monitor blood pressure and adjust as needed |
| CNS depressants | Potentiate sedating effects | Avoid use |
| Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers) | Potentiate bradycardia and risk of AV block | Avoid use |
|
|
|
|
|
|
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
|
|
|
|
|
| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
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|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
|
|
|
| Digoxin Enalapril Iron Metoprolol Warfarin |
|
|
|
|
| Ciprofloxacin Mycophenolate mofetil |
Take at least 2 hours before or 6 hours after sevelamer Take at least 2 hours before sevelamer |
|
|
|
|
| Carbamazepine | Decrease by 7 to 13%b) | Decrease by 19 to 26% Dependent on dose of carbamazepine |
| Lamotrigine | Decrease by 7 to 13%b) | No Effect |
| Phenobarbital | Increase by 8 to 13%b) | Decrease by 25 to 46%c)
’
d)
Independent of dose or concentration of phenobarbital |
| Phenytoin | Increase by 7 to 21%b) | Decrease by 25 to 46%c)
’
d)
Independent of dose or concentration of phenytoin |
| Topiramate | No Effect | No Effect |
| Valproate | No Effect | Increase by <16 to 70%c)
Dependent on concentration of valproate |
| Primidone | Not Investigated | Decrease by 25 to 46%c)
’
d)
Independent of dose or concentration of primidone |
| Benzodiazepines e) | Not Investigated | No Effect |
| a) Predictions are based on BANZEL concentrations at the maximum recommended dose of BANZEL. b) Maximum changes predicted to be in pediatric patients and in adult patients who achieve significantly higher levels of BANZEL, as the effect of rufinamide on these AEDs is concentration-dependent. c) Larger effects in pediatric patients at high doses/concentrations of AEDs. d) Phenobarbital, primidone and phenytoin were treated as a single covariate (phenobarbital-type inducers) to examine the effect of these agents on BANZEL clearance. e) All compounds of the benzodiazepine class were pooled to examine for ‘class effect’ on BANZEL clearance. |
||
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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Concentration Increase |
Increase |
Recommendations |
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The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
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Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
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Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. |
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Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted |
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A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. |
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Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. |
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Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy |
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Increased exposure of citalopram leading to an increased risk of QT prolongation |
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Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. |
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Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) |
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Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. |
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Potential for increased exposure of phenytoin. |
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Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. |
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Increased exposure of diazepam |
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Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
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Potential for increased exposure of digoxin |
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Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. |
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Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
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Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF See the prescribing information for other drugs dependent on gastric pH for absorption. |
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Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. |
| Amoxicillin also has drug interactions. | |
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See See |
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Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. |
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Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
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Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors |
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Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
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Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
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Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline |
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There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
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An alternative confirmatory method should be considered to verify positive results. |
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There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
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Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose |
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Hepatitis C protease inhibitor (boceprevir) |
|
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 50 mg (95% CI) |
|---|---|
| Supine | 9.08 (5.48, 12.68) |
| Standing |
11.62 (7.34, 15.90) |
| |
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Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see |
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| |
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see |
| |
Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see |
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| |
• During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. |
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| |
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
| |
During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see |
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| |
The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
| |
During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels. |
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| |
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
| |
During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity. |
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| |
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
| |
During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity. |
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| |
Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity. |
| |
During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function. |
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| |
Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see |
| |
The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended. |
| |
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| |
Concomitant use of mfenamic acid and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
| |
During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. |
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| |
In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively. |
| |
Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events. |
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Administer half of usual dose |
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|
Administer a quarter of usual dose |
|
Strong CYP2D6 |
Administer half of usual dose |
|
Strong CYP2D6 |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
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Drug |
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(Risperidone + 9- Hydroxy-Risperidone (Ratio |
Dose Recommendation |
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Drug |
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(CYP2D6) Inhibitors |
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twice daily |
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dosing. Do not exceed 8 mg/day |
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dosing. Do not exceed 8 mg/day |
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(CYP3A/PgP inducers) |
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mg/day |
daily |
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upwards. Do not exceed twice the patient’s usual dose |
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(CYP3A) Inhibitors |
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daily |
dose |
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not needed |
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daily |
dose |
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not needed |
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daily |
dose |
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not needed |
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daily |
daily |
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not needed |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio
|
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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See prescribing information for voriconazole. |
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Enalapril Iron Metoprolol Warfarin |
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| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| |
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| Carbamazepine | 400 to 2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 >1200 to 2400 | nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
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The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice |
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The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase |
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If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression. |
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Rifampin, carbamazepine, phenytoin |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome |
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The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs. |
| Drug/Drug Class (Mechanism of Interaction by Voriconazole) |
Drug Plasma Exposure (Cmax and AUCτ) |
Recommendations for Drug Dosage Adjustment/Comments |
| Sirolimus (CYP3A4 Inhibition) |
Significantly Increased |
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| Rifabutin (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (CYP3A4 Inhibition) |
Significantly Increased | When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See |
| High-dose Ritonavir (400 mg Q12h) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ |
|
| Low-dose Ritonavir (100mg Q12h) |
Slight Decrease in Ritonavir Cmax and AUCτ | Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased |
|
| Cyclosporine (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary (see |
| Tacrolimus (CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin (CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole (CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
No dosage adjustment for indinavir when coadministered with VFEND Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors |
| Other NNRTIs (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased | Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased | Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) | The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone
|
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage
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| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) | The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone
|
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage
|
| Antihypertensive Drugs | Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. | Monitor blood pressure and adjust dose accordingly
|
| Benzodiazepines(e.g., lorazepam) | The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone
|
Monitor sedation and blood pressure. Adjust dose accordingly. |
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| diltiazem | fluconazole | azithromycin | methylprednisolone | Allopurinol |
| nicardipine | itraconazole | clarithromycin | Amiodarone | |
| verapamil | ketoconazole | erythromycin | Bromocriptine | |
| voriconazole | quinupristin/ dalfopristin |
colchicine | ||
| danazol | ||||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
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| ↓= Decreased (induces lamotrigine glucuronidation). | ||
| ↑= Increased (inhibits lamotrigine glucuronidation). | ||
| ? = Conflicting data. | ||
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| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (
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| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding
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| Antidiabetic agents | Carefully monitor blood glucose (
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Drug Name |
Other Drugs |
|
| Thioridazine
|
Increased plasma concentrations of thioridazine
Potential QTc prolongation |
Concomitant use of thioridazine and BRISDELLE is
contraindicated. |
| Pimozide
|
Increased plasma concentrations
of pimozide. Potential QTc prolongation |
Concomitant use of pimozide and BRISDELLE is
contraindicated. |
| Tamoxifen
|
Reduced plasma concentrations
of active tamoxifen metabolite |
Consider avoiding concomitant use of tamoxifen
and BRISDELLE. |
|
Tricyclic Antidepressant (TCA) (e.g., Desipramine) |
Increased plasma concentrations
and elimination half-life |
Plasma TCA concentrations may need to be
monitored and the dose of TCA may need to be reduced if a TCA is co-administered with BRISDELLE. Monitor tolerability. |
| Risperidone
|
Increased plasma concentrations
of risperidone |
A lower dosage of risperidone may be necessary
(see the Full Prescribing Information for risperidone). Monitor tolerability. |
| Atomoxetine
|
Increased exposure of
atomoxetine |
A lower dosage of atomoxetine may be necessary
(see Full Prescribing Information for atomoxetine). Monitor tolerability. |
| Drugs Highly Bound
to Plasma Protein (e.g., Warfarin) |
Increased free plasma
concentrations |
The dosage of warfarin may need to be reduced.
Monitor tolerability and the International Normalized Ratio. |
| Digoxin
|
Decreased plasma concentrations
of digoxin |
Dosage of digoxin may need to be increased.
Monitor digoxin concentrations and clinical effect. |
| Theophylline
|
Increased plasma concentrations
of theophylline |
Dosage of theophylline may need to be decreased.
Monitor theophylline concentrations and tolerability. |
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|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
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|
|
| * For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. | |
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|
|
|
|
| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. |
|
| Allopurinol |
|
25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. |
|
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increase theophylline clearance. | 20% increase |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20 to 40% decrease |
| Sulfinpyrazone | Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% increase |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33 to 100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
|
|
| *Change relative to reference
|
|||||
| Coadministered Drug
|
Dosing Schedule
|
Effect on Active Moiety
(Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose
Recommendation |
||
| Coadministered Drug
|
Risperidone
|
AUC
|
Cmax
|
||
| Enzyme (CYP2D6) inhibitors
|
|
|
|
|
|
| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice daily
|
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
-
|
Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day
|
4 mg/day
|
1.6
|
-
|
||
| 40 mg/day
|
4 mg/day
|
1.8
|
-
|
||
| Enzyme (CYP3A/ PgP inducers) Inducers
|
|
|
|
|
|
| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) inhibitors
|
|
|
|
|
|
| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not needed
|
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not needed
|
| Erythromycin
|
500 mg four times daily
|
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not needed
|
| Other Drugs
|
|
|
|
|
|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not Needed
|
|
|
|
|
|
|
|
Glucocorticoids Octreotide |
|
|
|
|
|
|
|
|
Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
|
|
|
|
|
Iodide (including iodine-containing radiographic contrast agents) |
|
|
|
|
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
|
|
|
|
|
|
|
|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
|
|
|
|
|
|
|
|
Hydantoins Phenobarbital Rifampin |
|
|
|
|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
|
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
|
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
|
|
|
|
|
- Interferon-α - Interleukin-2 |
|
|
- Somatrem - Somatropin |
|
|
|
|
|
- (e.g., Theophylline) |
|
|
|
|
|
|
|
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
|
|
|
|||||
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
|
|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
|
|
||
|
|
||
|
|
||
|
|
|
|
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and
150 mcg levonorgestrel |
↓ lamotrigine
↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide
|
↓ lamotrigine
? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 50%.
|
| Atazanavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine AUC approximately 32%.
|
| Phenobarbital/primidone
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 40%.
|
| Phenytoin
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 40%.
|
| Rifampin
|
↓ lamotrigine
|
Decreased lamotrigine AUC approximately 40%.
|
| Valproate
|
↑ lamotrigine
? valproate |
Increased lamotrigine concentrations slightly more than 2-fold.
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
|
|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| Calcitriol
Ciprofloxacin Digoxin Enalapril Furosemide HMG-CoA reductase inhibitors Hydrochlorothiazide Losartan Metoprolol Nifedipine Omeprazole Quinidine Warfarin |
|
|
Oral drugs that are to be separated from Velphoro and meals |
|
|
|
|
| Doxycycline | Take at least 1 hour before Velphoro. |
|
|
|
| Levothyroxine | |
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine
|
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (
|
| Warfarin
|
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
|
| Antidiabetic agents
|
Carefully monitor blood glucose (
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Norepinephrine Dopamine |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
|
|
|
|
|
| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine
|
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
|
| Warfarin
|
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
|
| Antidiabetic agents
|
Carefully monitor blood glucose (
|
|
|
|
|
|
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
|
|
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
|
|
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
|
|
|
|
|
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
|
|
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Injection if serotonin syndrome is suspected. |
|
|
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
|
|
|
|
|
MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) |
|
|
Do not use Morphine Sulfate Injection in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of |
|
|
phenelzine, tranylcypromine, linezolid |
|
|
|
|
|
May reduce the analgesic effect of Morphine Sulfate Injection and/or precipitate withdrawal symptoms. |
|
|
Avoid concomitant use. |
|
|
butorphanol, nalbuphine, pentazocine, buprenorphine. |
|
|
|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
|
|
The concomitant use of tramadol hydrochloride and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome.
After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression |
|
|
If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome.
If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation. |
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Quinidine, fluoxetine, paroxetine and bupropion
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The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved.
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
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The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase |
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If concomitant use is necessary, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride and acetaminophen and carbamazepine is not recommended. |
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Rifampin, carbamazepine, phenytoin
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride and acetaminophen if serotonin syndrome is suspected.
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
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MAOI interactions with opioids may manifest as serotonin syndrome
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Do not use tramadol hydrochloride and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment.
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phenelzine, tranylcypromine, linezolid
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May reduce the analgesic effect of tramadol hydrochloride and acetaminophen and/or precipitate withdrawal symptoms.
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Avoid concomitant use.
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butorphanol, nalbuphine, pentazocine, buprenorphine
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Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride and acetaminophen and/or the muscle relaxant as necessary.
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
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Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride and acetaminophen is used concomitantly with anticholinergic drugs.
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Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
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Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
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Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
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Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.
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Monitor patients with concomitant use of MOBIC with anticoagulants
(e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin
reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake
inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant
use of NSAIDs and analgesic doses of aspirin does not produce any
greater therapeutic effect than the use of NSAIDs alone. In a clinical
study, the concomitant use of an NSAID and aspirin was associated
with a significantly increased incidence of GI adverse reactions as
compared to use of the NSAID alone [ |
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Concomitant
use of MOBIC and low dose aspirin or analgesic doses of aspirin is
not generally recommended because of the increased risk of bleeding
[ MOBIC is not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of MOBIC with diuretics, observe
patients for signs of worsening renal function, in addition to assuring
diuretic efficacy including antihypertensive effects [ |
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NSAIDs have produced elevations in plasma lithium levels
and reductions in renal lithium clearance. The mean minimum lithium
concentration increased 15%, and the renal clearance decreased by
approximately 20%. This effect has been attributed to NSAID inhibition
of renal prostaglandin synthesis [ |
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During concomitant use of MOBIC and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of MOBIC and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of MOBIC and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of MOBIC and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates
(e.g., diflunisal, salsalate) increases the risk of GI toxicity, with
little or no increase in efficacy [ |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of MOBIC and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of MOBIC and pemetrexed, in patients
with renal impairment whose creatinine clearance ranges from 45 to
79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
|
| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
|
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use. Monitor serum level ( |
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|
prothrombin time, INR, and bleeding ( |
|
|
reported. Monitor blood glucose ( |
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creatinine ( |
|
products including antacids, metal cations or didanosine |
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|
|
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome. |
|
|
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue |
|
|
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
|
|
|
|
|
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias. |
|
|
Concomitant use of pimozide and sertraline hydrochloride is contraindicated |
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|
|
|
|
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome. |
|
|
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs |
|
|
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort |
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|
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding. |
|
|
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio |
|
|
aspirin, clopidogrel, heparin, warfarin |
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|
|
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma |
|
|
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted. |
|
|
warfarin |
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|
|
Sertraline hydrochloride is a CYP2D6 inhibitor |
|
|
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued. |
|
|
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine |
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|
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|
|
Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations. |
|
|
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed. |
|
|
phenytoin, fosphenytoin |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
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|
||
| Atazanavir/Ritonavir* |
↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* Fosamprenavir/Ritonavir* |
↓Amprenavir ↑Nevirapine ↓Amprenavir ↑Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* |
↓ Indinavir |
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* |
↓ Lopinavir |
Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* |
↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir |
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated |
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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|
||
| Efavirenz* Delavirdine Etravirine Rilpivirine |
↓Efavirenz |
The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
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| Boceprevir |
Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. |
Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy. |
| Telaprevir |
Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. |
Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events. |
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|
Methadone* |
↓Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Clarithromycin* Rifabutin* Rifampin* |
↓Clarithromycin ↑14-OH clarithromycin ↑Rifabutin ↓ Nevirapine |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* Ketoconazole* Itraconazole |
↑Nevirapine ↓ Ketoconazole ↓ Itraconazole |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
|
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception. When these oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored. |
| * The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (> 1 quart daily) |
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• Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
| |
Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Celecoxib is not a substitute for low dose aspirin for cardiovascular protection. |
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• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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• During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of celecoxib and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
|
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During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
| |
During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity. |
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|
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Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function. |
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|
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Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. |
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|
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Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ |
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Evaluate each patient’s medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ |
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Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [ |
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There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. |
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Closely monitor patients with concurrent use of buprenorphine and naloxone sublingual tablets and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine and naloxone sublingual tablets, and warn patients to use benzodiazepines concurrently with buprenorphine and naloxone sublingual tablets only as directed by their healthcare provider. |
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Due to additive pharmacologic effects, the concomitant use of non-benzodiazepine CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids. |
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The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine and naloxone sublingual tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of buprenorphine and naloxone sublingual tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine and naloxone sublingual tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
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The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase |
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If concomitant use is necessary, consider increasing the buprenorphine and naloxone sublingual tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider buprenorphine and naloxone sublingual tablets dosage reduction and monitor for signs of respiratory depression. |
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Rifampin, carbamazepine, phenytoin |
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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. |
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Patients who are on chronic buprenorphine and naloxone sublingual tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimen. |
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efavirenz, nevirapine, etravirine, delavirdine |
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Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. |
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Monitor patients taking buprenorphine and naloxone sublingual tablets and atazanavir with and without ritonavir, and reduce dose of buprenorphine and naloxone sublingual tablets if warranted. |
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atazanavir, ritonavir |
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Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. |
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None |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine and naloxone sublingual tablets if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma). |
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The use of buprenorphine and naloxone sublingual tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients receiving muscle relaxants and buprenorphine and naloxone sublingual tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine and naloxone sublingual tablets and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine and naloxone sublingual tablets are used concomitantly with anticholinergic drugs. |
| a) This table is not all inclusive. | |
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| carbamazepine | rifabutin |
| phenobarbital | caspofungin |
| phenytoin | rifampin |
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| St. John’s Wort | sirolimus |
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| Antacids, sucralfate, multivitamins, and other products containing multivalent cations | Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin | Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
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| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
|
Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
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| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| blood dyscrasias - see cancer collagen vascular disease congestive heart failure |
diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice |
hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency |
| blood dyscrasias - see cancer collagen vascular disease congestive heart failure
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diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice
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hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency
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| HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir |
↓ amprenavir
↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor:
indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily
|
| HIV-1 Protease Inhibitor:
nelfinavir* |
↑ nelfinavir
↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir
|
| HIV-1 Protease Inhibitor:
ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor:
saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor:
tipranavir |
↓ lopinavir AUC and C min | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – Antagonist:
maraviroc |
↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry ® (maraviroc). |
| Non-nucleoside Reverse Transcriptase Inhibitor:
etravirine |
↓ etravirine | Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, no dose adjustment is required. |
| Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Non-nucleoside Reverse Transcriptase Inhibitor:
rilpivirine |
↑ rilpivirine | No dose adjustment is required. |
| Nucleoside Reverse Transcriptase Inhibitor:
didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor:
tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitors:
abacavir zidovudine |
↓ abacavir
↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
|
|
||
| Antiarrhythmics e.g.:
amiodarone, bepridil, lidocaine (systemic), quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents:
vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulants:
warfarin, rivaroxaban |
↑ rivaroxaban | Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding. |
| Anticonvulsants:
carbamazepine, phenobarbital, phenytoin |
↓ lopinavir
↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Anticonvulsants:
lamotrigine, valproate |
↓ lamotrigine
↓ or ↔ valproate |
Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments. |
| Antidepressant:
bupropion |
↓ bupropion
↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant:
trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective:
clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered:
|
| Antifungals:
ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole
↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout:
colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA.
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial:
bedaquiline |
↑ bedaquiline | Bedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk
|
| Antimycobacterial:
rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial:
rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone
|
| Antiparasitic:
atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Antipsychotics: quetiapine | ↑ quetiapine |
Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam
|
| Contraceptive:
ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroids (systemic): e.g.
budesonide, dexamethasone, prednisone |
↓ lopinavir
↑ glucocorticoids |
Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. |
| Dihydropyridine Calcium Channel Blockers: e.g.
felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists:
bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HCV-Protease Inhibitor:
boceprevir |
↓ lopinavir
↓ boceprevir ↓ ritonavir |
It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures
|
| HCV-Protease Inhibitor:
simeprevir |
↑ simeprevir | It is not recommended to co-administer KALETRA and simeprevir. |
| HMG-CoA Reductase Inhibitors:
atorvastatin rosuvastatin |
↑ atorvastatin
↑ rosuvastatin |
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA
|
| Immunosuppressants: e.g.
cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled or Intranasal Steroids e.g.:
fluticasone, budesonide |
↑ glucocorticoids | Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide. |
| Long-acting beta-adrenoceptor Agonist:
salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesics:
methadone,* fentanyl |
↓ methadone
↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors:
avanafil, sildenafil, tadalafil, vardenafil |
↑ avanafil
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established.
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio ®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca ®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
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| Known CYP2D6 Poor Metabolizers | Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP2D6 |
Administer half of usual dose |
| Strong CYP2D6 |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
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| DRUG | DESCRIPTION OF INTERACTION |
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. |
| Acidifying Agents | Increases plasma salicylate level. |
| Alkalizing Agents | Decreased plasma salicylate levels. |
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| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
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fibrates, gemfibrozil |
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digoxin |
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| ciprofloxacin | melphalan | amphotericin B | azapropazon | cimetidine | tacrolimus | fibric acid derivatives (e.g., bezafibrate, fenofibrate) |
| gentamicin | ketoconazole | colchicine | ranitidine | methotrexate | ||
| tobramycin | diclofenac | |||||
| trimethoprim with sulfamethoxazole |
naproxen | |||||
| vancomycin | sulindac |
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| Anticoagulants
|
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
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| Antiplatelet Agents
|
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
|
| Nonsteroidal Anti-Inflammatory Agents
|
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
|
| Serotonin Reuptake Inhibitors
|
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Sulfonylureas | Hypoglycemia potentiated. | ||
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. | ||
| Oral Anticoagulants | Increased bleeding. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. | ||
| Acidifying Agents | Increases plasma salicylate levels. | ||
| Alkanizing Agents | Decreased plasma salicylate levels. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. | ||
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. | ||
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. | ||
| The following alterations of laboratory tests have been reported during salicylate therapy: | |||
| LABORATORY TESTS | EFFECT OF SALICYLATES | ||
| Thyroid Function | Decreased PBI; increased t3 uptake. | ||
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). | ||
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. | ||
| Acetone ketone bodies | False positive FeCI3 in Gerhardt reaction; red color persists with boiling. | ||
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. | ||
| Vanilmandelic acid | False reduced values. | ||
| Uric Acid | May increase or decrease depending on dose. | ||
| Prothrombin | Decreased levels; slightly increased prothrombin time. | ||
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide
|
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
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Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Anticoagulants
|
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
|
| Antiplatelet Agents
|
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
|
| Nonsteroidal Anti-Inflammatory Agents
|
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
|
| Serotonin Reuptake Inhibitors
|
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone
|
| |
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| Erythromycin (500 mg every 8 hrs) | +82% | +109% |
| Ketoconazole (400 mg once daily) | +135% | +164% |
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| blood dyscrasias - see cancer collagen vascular disease congestive heart failure |
diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice |
hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency |
| Recommended CERDELGA Dosage, by CYP2D6 Metabolizer Status | ||
|---|---|---|
| CYP450 Inhibitors | EM | IM |
|
|
Contraindicated | Contraindicated |
|
e.g., paroxetine |
84 mg once daily | 84 mg once daily |
|
e.g., terbinafine |
84 mg once daily | 84 mg once daily |
|
e.g., ketoconazole |
84 mg once daily | Contraindicated |
|
e.g., fluconazole |
84 mg once daily | Not recommended |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
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|
Decreased exposure of omeprazole when used concomitantly with strong inducers
|
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|
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole
Ritonavir-containing products: see prescribing information for specific drugs. |
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Increased exposure of omeprazole
|
|
|
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
See prescribing information for voriconazole. |
|
|
Dofetilide | Concomitant administration with digoxin was associated with a higher rate of torsades de pointes. |
| Moricizine | Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction. | |
| Sotalol | Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. | |
|
|
Teriparatide | Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. |
|
|
Thyroid | Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. |
|
|
Epinepherine | Can increase the risk of cardiac arrhythmias. |
| Norepinephrine | ||
| Dopamine | ||
|
|
Succinylcholine | May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin. |
|
|
Calcium | If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. |
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Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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|
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
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|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
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|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| quinupristin/ | colchicine | |||
| voriconazole | dalfopristin | danazol | ||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
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Monitor patients with concomitant use of VOLTAREN® GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone |
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Concomitant use of VOLTAREN® GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding |
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• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme |
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• During concomitant use of VOLTAREN® GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. | ||
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During concomitant use of VOLTAREN® GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects |
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The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. | ||
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During concomitant use of VOLTAREN® GEL and digoxin, monitor serum digoxin levels. | ||
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. | ||
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During concomitant use of VOLTAREN® GEL and lithium, monitor patients for signs of lithium toxicity. | ||
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). | ||
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During concomitant use of VOLTAREN® GEL and methotrexate, monitor patients for methotrexate toxicity. | ||
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Concomitant use of VOLTAREN® GEL and cyclosporine may increase cyclosporine's nephrotoxicity. | ||
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During concomitant use of VOLTAREN® GEL and cyclosporine, monitor patients for signs of worsening renal function. | ||
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Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy |
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The concomitant use of diclofenac with other NSAIDs or salicylates is notrecommended. | ||
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Concomitant use of VOLTAREN® GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). | ||
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During concomitant use of VOLTAREN® GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. |
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| *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. | |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily* |
| Grapefruit juice |
Avoid grapefruit juice |
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Name or Drug Class |
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(e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
tablets with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone PHARMACOLOGY ( |
aripiprazole tablets with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole tablets dosage ADMINISTRATION ( |
|
(e.g., carbamazepine, rifampin) |
tablets and carbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone |
aripiprazole tablets with a strong CYP3A4 inducer, consider increasing the aripiprazole tablets dosage ADMINISTRATION ( |
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aripiprazole tablets has the potential to enhance the effect of certain antihypertensive agents. |
adjust dose accordingly PRECAUTIONS ( |
|
Benzodiazepines (e.g., lorazepam) |
the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone.The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone WARNINGS AND PRECAUTIONS ( |
pressure. Adjust dose accordingly. |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
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Hepatitis C protease inhibitor (boceprevir) |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
|
Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| Drug/Drug Class (Mechanism of Interaction by Voriconazole) |
Drug Plasma Exposure (Cmax and AUCτ) |
Recommendations for Drug Dosage Adjustment/Comments |
|---|---|---|
| Sirolimus (CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (400 mg q24h) (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (300 mg q24h) (CYP3A4 Inhibition) |
Slight Increase in AUCτ | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ |
|
| Low-dose Ritonavir (100 mg q12h) |
Slight Decrease in Ritonavir Cmax and AUCτ | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
|
| Cyclosporine (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) | Increased | Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary |
| Oxycodone (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary |
| NSAIDs (CYP2C9 Inhibition) |
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed |
| Tacrolimus (CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin (CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole (CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment for indinavir when coadministered with VFEND |
|
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors | |
| Other NNRTIs (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
| Everolimus (CYP3A4 Inhibition) |
Not Studied |
Concomitant administration of voriconazole and everolimus is not recommended. |
| albuterol, | diltiazem | medroxyprogesterone | roxithromycin |
| systemic and inhaled | dirithromycin | methylprednisolone | sorbitol |
| amoxicillin | enflurane | metronidazole | (purgative doses |
| ampicillin, | famotidine | metoprolol | do not inhibit |
| with or without | felodipine | nadolol | theophylline |
| sulbactam | finasteride | nifedipine | absorption) |
| atenolol | hydrocortisone | nizatidine | sucralfate |
| azithromycin | isoflurane | norfloxacin | terbutaline, systemic |
| caffeine, | isoniazid | ofloxacin | terfenadine |
| dietary ingestion | isradipine | omeprazole | tetracycline |
| cefaclor | influenza vaccine | prednisone, | tocainide |
| co-trimoxazole | ketoconazole | prednisolone | |
| (trimethoprim and | lomefloxacin | ranitidine | |
| sulfamethoxazole) | mebendazole | rifabutin | |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide
|
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
|
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
|
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment | |
|---|---|---|---|
| HIV-Antiviral Agents | |||
| Non-nucleoside Reverse Transcriptase Inhibitors: | Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. | ||
| delavirdine | ↑ nelfinavir ↓ delavirdine |
||
| nevirapine | ↓ nelfinavir (Cmin) | ||
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food). |
||
| Protease Inhibitors: | Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. | ||
| indinavir | ↑ nelfinavir ↑ indinavir |
||
| ritonavir | ↑ nelfinavir | ||
| saquinavir | ↑ saquinavir | ||
| Other Agents | |||
| Anti-coagulant: warfarin |
warfarin | Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy. | |
| Anti-convulsants: | May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. | ||
| carbamazepine phenobarbital |
↓ nelfinavir | ||
| Anti-convulsant: | Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration. | ||
| phenytoin | ↓ phenytoin | ||
| Anti-depressant: trazodone | ↑ trazodone | Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered. | |
| Anti-gout colchicine |
↑ colchicine | Treatment of gout flares– coadministration of colchicine in patients on VIRACEPT: coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. coadministration of colchicine in patients on VIRACEPT: Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT. |
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| Anti-Mycobacterial: | It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin. | ||
| rifabutin | ↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID) |
||
| Endothelin receptor antagonists: bosentan |
↑ bosentan |
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| HMG-CoA Reductase Inhibitor: | Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT. | ||
| atorvastatin | ↑ atorvastatin | ||
| rosuvastatin | ↑ rosuvastatin | ||
| Immuno-suppressants: | Plasma concentrations may be increased by VIRACEPT. | ||
| cyclosporine tacrolimus sirolimus |
↑ immuno-suppressants | ||
| Inhaled beta agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. | |
| Inhaled/nasal steroid: Fluticasone | ↑ fluticasone | Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. | |
| Macrolide Antibiotic: azithromycin |
↑ azithromycin |
Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted. | |
| Narcotic Analgesic: | Dosage of methadone may need to be increased when coadministered with VIRACEPT. | ||
| methadone | ↓ methadone | ||
| Oral Contraceptive: | Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered. | ||
| ethinyl estradiol | ↓ ethinyl estradiol | ||
| PDE5 Inhibitors: sildenafil vardenafil tadalafil |
↑ PDE5 Inhibitors |
Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution.
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In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg). |
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Celecoxib is not a substitute for low dose aspirin for cardiovascular protection. |
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NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice. |
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If concomitant use is necessary, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Fentanyl Citrate Injection dosage reduction and monitor for signs of respiratory depression. |
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Rifampin, carbamazepine, phenytoin |
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The concomitant use of Fentanyl Citrate Injection with CNS depressants my result in decreased pulmonary artery pressure and may cause hypotension. Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Fentanyl Citrate Injection. As postoperative analgesia, concomitant use of Fentanyl Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, barbiturates, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).. |
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MAOI interactions with opioids may manifest as serotonin syndrome |
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The use of Fentanyl Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
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Phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of Fentanyl Citrate Injection and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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Butorphanol, nalbuphine, pentazocine, buprenorphine. |
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Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus |
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Monitor patients for signs of urinary retention or reduced gastric motility when Fentanyl Citrate Injection is used concomitantly with anticholinergic drugs |
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Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Fentanyl Citrate Injection combined with a neuroleptic |
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ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Fentanyl Citrate Injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia. |
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Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Fentanyl Citrate Injection. |
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Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected. |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| Clinical Impact: | Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. | |
| Intervention: |
Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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| Clinical Impact: |
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
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| Intervention: |
Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
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| Clinical Impact: | NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. | |
| Intervention: |
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [
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| Clinical Impact: |
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [
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| Intervention: |
Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [
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| Clinical Impact: | The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. | |
| Intervention: | During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. | |
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| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. | |
| Intervention: | During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. | |
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| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). | |
| Intervention: | During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity. | |
| Intervention: | During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. | |
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| Clinical Impact: |
Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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| Intervention: | The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). | |
| Intervention: | During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. | |
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| Clinical Impact: | When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. | |
| Intervention: | During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. | |
| Drug | Effect |
| Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). | Cardiac pressor response potentiated. May cause acute hypertensive crisis. |
| Phenylephrine with tricyclic antidepressants. | Pressor response increased. |
| Phenylephrine with ergot alkaloids. | Excessive rise in blood pressure. |
| Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. | Tachycardia or other arrhythmias may occur. |
| Phenylephrine with prior administration of propranolol or other β-adrenergic blockers. | Cardiostimulating effects blocked. |
| Phenylephrine with atropine sulfate. | Reflex bradycardia blocked; pressor response enhanced. |
| Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. | Pressor response decreased. |
| Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. | Synergistic adrenergic response. |
| Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment | |
|---|---|---|---|
| HIV-Antiviral Agents | |||
| Protease Inhibitors: | Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. | ||
| indinavir | ↑ nelfinavir ↑ indinavir |
||
| ritonavir | ↑ nelfinavir | ||
| saquinavir | ↑ saquinavir | ||
| Non-nucleoside Reverse Transcriptase Inhibitors: | Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. | ||
| delavirdine | ↑ nelfinavir ↓ delavirdine |
||
| nevirapine | ↓ nelfinavir (Cmin) | ||
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food). |
||
| Other Agents | |||
| Anti-Convulsants: | May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. | ||
| carbamazepine phenobarbital |
↓ nelfinavir | ||
| Anti-Convulsant: | Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration. | ||
| phenytoin | ↓ phenytoin | ||
| Anti-Mycobacterial: | It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin. | ||
| rifabutin | ↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID) |
||
| PDE5 Inhibitors: sildenafil vardenafil tadalafil |
↑ PDE5 Inhibitors | Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. If concomitant use of PDE5 inhibitors and VIRACEPT is required, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. | |
| HMG-CoA Reductase Inhibitor: | Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT. | ||
| atorvastatin | ↑ atorvastatin | ||
| rosuvastatin | ↑ rosuvastatin | ||
| Immuno-suppressants: | Plasma concentrations may be increased by VIRACEPT. | ||
| cyclosporine tacrolimus sirolimus |
↑ immuno-suppressants | ||
| Narcotic Analgesic: | Dosage of methadone may need to be increased when coadministered with VIRACEPT. | ||
| methadone | ↓ methadone | ||
| Oral Contraceptive: | Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered. | ||
| ethinyl estradiol | ↓ ethinyl estradiol | ||
| Macrolide Antibiotic: azithromycin |
↑ azithromycin |
Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted. | |
| Inhaled/nasal steroid: Fluticasone | ↑ fluticasone | Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. | |
| Antidepressant: trazodone | ↑ trazodone | Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered. | |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Saquinavir or Concomitant Drug | Clinical Comment |
|---|---|---|
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Delavirdine |
↑ Saquinavir Effect on delavirdine is not well established |
Appropriate doses of the combination with respect to safety and efficacy have not been established. |
|
Efavirenz nevirapine |
↓ Saquinavir ↔ Efavirenz |
Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir (1000/100 mg bid) with respect to safety and efficacy have not been established. |
|
Atazanavir |
↑ Saquinavir ↑ Ritonavir ↔ Atazanavir |
Appropriate dosing recommendations for this combination, with respect to efficacy and safety, have not been established. When 1600 mg INVIRASE/100 mg ritonavir and 300 mg atazanavir were coadministered, plasma concentrations of saquinavir and ritonavir were increased. |
|
Indinavir |
↑ Saquinavir Effect on indinavir is not well established |
Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established. |
|
Lopinavir/ritonavir |
↔ Saquinavir ↔ Lopinavir ↓ Ritonavir |
Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid. |
|
Tipranavir/ritonavir |
↓ Saquinavir | Combining saquinavir with tipranavir/ritonavir is not recommended. |
|
Enfuvirtide |
Saquinavir soft gel capsules/ritonavir ↔ enfuvirtide |
No clinically significant interaction was noted from a study in 12 HIV patients who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required. |
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Lidocaine (systemic) |
↑ Antiarrhythmics | Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics given with INVIRASE/ritonavir. |
|
Warfarin |
↑ Warfarin | Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. |
|
Carbamazepine |
↓ Saquinavir Effect on carbamazepine, phenobarbital, and phenytoin is not well established |
Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. |
|
Clarithromycin |
↑ Saquinavir ↑ Clarithromycin |
Appropriate doses of the combination of clarithromycin and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended: For patients with renal impairment, the following dosage adjustments should be considered:
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Ketoconazole |
↔ Saquinavir ↔ Ritonavir ↑ Ketoconazole |
Appropriate doses of the combination of ketoconazole or itraconazole and INVIRASE/ritonavir with respect to safety and efficacy have not been established. When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentration of ketoconazole was increased (see |
|
Rifabutin |
↓ Saquinavir ↑ Rifabutin |
Appropriate doses of the combination of rifabutin and INVIRASE/ritonavir with respect to safety and efficacy have not been established. |
|
Alprazolam, clorazepate, diazepam, flurazepam |
↑ Benzodiazepines | Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed. |
|
Intravenously administered Midazolam |
↑ Midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam [see |
|
Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine |
↑ Calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
|
Dexamethasone |
↓ Saquinavir | Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. |
|
Digoxin |
↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir. |
Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir (see |
|
Fluticasone |
↑ Fluticasone |
Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see |
|
Atorvastatin, rosuvastatin |
↑ Atorvastatin ↑ Rosuvastatin |
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with Invirase/ritonavir (see |
|
Cyclosporine, tacrolimus, rapamycin |
↑ Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir. |
|
Methadone |
↓ Methadone | Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir. |
|
Ethinyl estradiol |
↓ Ethinyl estradiol | Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered. |
|
Sildenafil |
↑ Sildenafil ↔ Saquinavir ↑ Vardenafil ↑ Tadalafil |
Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. |
|
Trazodone |
↑ Trazodone | Concomitant use of trazodone and INVIRASE/ritonavir may increase plasma concentration of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as INVIRASE/ritonavir, the combination should be used with caution and lower dose of trazodone should be considered. |
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↑ Tricyclics | Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir. |
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↑ Saquinavir | When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis. |
|
St. John's wort |
↓ Saquinavir | Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors (see |
| Garlic Capsules |
↓ Saquinavir | Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations. |
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Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (
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Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. |
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Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis |
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Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. |
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Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). |
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Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
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Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
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Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
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Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
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Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
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These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
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| Grapefruit juice | Avoid grapefruit juice |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ |
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During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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Glucocorticoids Octreotide |
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Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
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Iodide(including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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| CYP2C9
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amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
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aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
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| CYP1A2
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acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
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montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
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| CYP3A4
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alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
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armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide
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The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression |
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If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation. |
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Quinidine, fluoxetine, paroxetine and bupropion |
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The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
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The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase |
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If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended. |
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Rifampin, carbamazepine, phenytoin |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome |
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Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets are used concomitantly with anticholinergic drugs. |
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Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity. |
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Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed. |
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Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times. |
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Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed. |
| Increased Risk of Myopathy/Rhabdomyolysis ( |
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|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| Lopinavir plus ritonavir | Use lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) | Do not exceed 40 mg atorvastatin daily |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone (Ratio |
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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| Strong CYP2D6 or CYP3A4 inhibitors | Administer half of usual dose |
| Strong CYP2D6 and CYP3A4inhibitors | Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
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|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
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| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [
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| Theophylline | Avoid Use
(Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate.
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| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)
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| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated | Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (
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| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) | To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. | ||
| Cyclosporine | Use with caution (transient elevations in serum creatinine) | Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. | ||
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) | The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). | ||
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels | Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. | ||
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see
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| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. | ||
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. | ||
| Sildenafil | Use with caution Two-fold increase in exposure | Monitor for sildenafil toxicity (see
|
||
| Duloxetine | Avoid Use
Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity | ||
| Caffeine/Xanthine Derivatives | Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life | Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. | ||
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|
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| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration
|
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
|
||
| Probenecid
|
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)
|
Potentiation of ciprofloxacin toxicity may occur.
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| Clinical Impact: | The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology • There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. |
| Intervention: | Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs. |
| |
|
| Clinical Impact: | Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
| Intervention: | Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. |
| |
|
| Clinical Impact: | Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions |
| Intervention: | A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. |
| |
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| |
|
| Clinical Impact: | Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [ There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. |
| Intervention: | Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions |
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|
| Clinical Impact: | Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology |
| Intervention: | Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. |
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|
| Clinical Impact: | Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology |
| Intervention: | Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. |
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| Clinical Impact: | Potential for increased exposure of phenytoin. |
| Intervention: | Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. |
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| Clinical Impact: | Increased exposure of diazepam [see Clinical Pharmacology |
| Intervention: | Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
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| Clinical Impact: | Potential for increased exposure of digoxin [see Clinical Pharmacology |
| Intervention: | Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. |
| |
|
| Clinical Impact: | Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
| Intervention: | Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology |
| |
|
| Clinical Impact: | Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. |
| Intervention: | See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin. |
| |
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| Clinical Impact: | Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. |
| Intervention: | Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
| |
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| Clinical Impact: | Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions |
| Intervention: | Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
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| Clinical Impact: | Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
| Intervention: | Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology |
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| Clinical Impact: | There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
| Intervention: | An alternative confirmatory method should be considered to verify positive results. |
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| Clinical Impact: | There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
| Intervention: | Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Drug | Description of Interaction |
| Tolbutamide; Sulfonylureas | Hypoglycemia potentiated |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result |
| Oral Anticoagulant | Increased bleeding |
| |
|
| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| edema hereditary coumarin resistance hyperlipemia |
hypothyroidism nephrotic syndrome |
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| Phenytoin
|
NCor25%increase
a
|
48%decrease
|
| Carbamazepine(CBZ)
|
NC
|
40%decrease
|
| CBZepoxide
b
|
NC
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NE
|
| Valproic acid
|
11%decrease
|
14%decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
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NE
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| Lamotrigine
|
NCatTPM dosesupto400 mg/day
|
13%decrease
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See prescribing information for voriconazole. |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
Concentration of Lamotrigine or Concomitant Drug |
|
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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| valsartan*
losartan* candesartan* |
↑ angiotensin receptor blockers | Decrease the dose of the angiotensin receptor blockers and monitor patients for signs and symptoms of hypotension and/or worsening renal function. If such events occur, consider further dose reduction of the angiotensin receptor blocker or switching to an alternative to the angiotensin receptor blocker. |
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| amiodarone*, bepridil*, disopyramide*, flecainide*, lidocaine (systemic)*, mexiletine*, propafenone*, quinidine* |
↑ antiarrhythmics | For contraindicated antiarrhythmics Therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with VIEKIRA PAK. |
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| metformin | ↔ metformin | Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Concomitant metformin use in patients with renal insufficiency or hepatic impairment is not recommended. Refer to the prescribing information of metformin for further guidance. |
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| ketoconazole | ↑ ketoconazole | When VIEKIRA PAK is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day. |
| voriconazole* | ↓ voriconazole | Co-administration of VIEKIRA PAK with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole. |
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| quetiapine* | ↑ quetiapine | For contraindicated antipsychotics
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| amlodipine nifedipine* diltiazem* verapamil* |
↑ calcium channel blockers | Decrease the dose of the calcium channel blocker. The dose of amlodipine should be decreased by at least 50%. Clinical monitoring of patients is recommended for edema and/or signs and symptoms of hypotension. If such events occur, consider further dose reduction of the calcium channel blocker or switching to an alternative to the calcium channel blocker. |
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| fluticasone* | ↑ fluticasone | Concomitant use of VIEKIRA PAK with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use. |
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| furosemide | ↑ furosemide (Cmax) | Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response. |
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| atazanavir/ritonavir once daily |
↑ paritaprevir | When coadministered with VIEKIRA PAK, atazanavir 300 mg (without ritonavir) should only be given in the morning. |
| darunavir/ritonavir | ↓ darunavir (Ctrough) | Treatment naïve patients or treatment experienced patients with no darunavir associated substitutions: Darunavir 800 mg once daily (without ritonavir) can be co-administered with VIEKIRA PAK. Treatment experienced patients with at least one darunavir resistance associated substitution or with no baseline resistance information: Co-administration of darunavir/ritonavir 600/100 mg twice daily with VIEKIRA PAK is not recommended. |
| lopinavir/ritonavir | ↑ paritaprevir | Co-administration of VIEKIRA PAK with lopinavir/ritonavir is not recommended. |
| rilpivirine | ↑ rilpivirine | For contraindicated non-nucleoside reverse transcriptase inhibitors Co-administration of VIEKIRA PAK with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine. |
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| rosuvastatin | ↑ rosuvastatin | For contraindicated HMG-CoA Reductase Inhibitors When VIEKIRA PAK is co-administered with rosuvastatin, the dose of rosuvastatin should not exceed 10 mg per day. |
| pravastatin | ↑ pravastatin | When VIEKIRA PAK is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day. |
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| cyclosporine | ↑ cyclosporine | For contraindicated immunosuppressants When initiating therapy with VIEKIRA PAK, reduce cyclosporine dose to 1/5th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of VIEKIRA PAK therapy, the appropriate time to resume pre-VIEKIRA PAK dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended. |
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| salmeterol* | ↑ salmeterol | Concurrent administration of VIEKIRA PAK and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
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| carisoprodol | ↓ carisoprodol ↔ mepobramate (metabolite of carisoprodol) |
Increase dose if clinically indicated. |
| cyclobenzaprine | ↓cyclobenzaprine ↓norcyclobenzaprine (metabolite of cyclobenzaprine) |
Increase dose if clinically indicated. |
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| buprenorphine/ naloxone |
↑ buprenorphine ↑ norbuprenorphine (metabolite of buprenorphine) |
Patients should be closely monitored for sedation and cognitive effects. |
| Acetaminophen/ hydrocodone |
↑ hydrocodone ↔ acetaminophen |
Reduce the dose of hydrocodone by 50% and monitor patients for respiratory depression and sedation at frequent intervals. Upon completion of VIEKIRA PAK therapy, adjust the hydrocodone dose and monitor for signs of opioid withdrawal. |
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| omeprazole | ↓ omeprazole | Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole. |
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| alprazolam | ↑ alprazolam | For contraindicated Sedatives/Hypnotics Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response. |
| diazepam | ↓ diazepam ↓ nordiazepam (metabolite of diazepam) |
Increase dose if clinically indicated. |
|
The direction of the arrow indicates the direction of the change in exposures (Cmax and AUC) (↑ = *not studied. |
||
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| |
|
|
| Phenytoin |
NCor25%increasea
|
48%decrease |
| Carbamazepine(CBZ) |
NC |
40%decrease |
| CBZepoxideb
|
NC |
NE |
| Valproic acid |
11%decrease |
14%decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NCatTPM dosesupto400 mg/day |
13%decrease |
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine
|
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (
|
| Warfarin
|
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
|
| Antidiabetic agents
|
Carefully monitor blood glucose (
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| AED Coadministered | Dose of AED (mg/day) |
Oxcarbazepine Dose (mg/day) |
Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) |
Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc |
40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc up to 40% increase [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc |
18% decrease [CI: 13% decrease, 40% decrease] |
|
|
|
| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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Nevirapine or Concomitant Drug |
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| Atazanavir/Ritonavir* |
↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with
atazanavir because nevirapine substantially decreases atazanavir exposure
and there is a potential risk for nevirapine-associated toxicity due
to increased nevirapine exposures. |
| Fosamprenavir* |
↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir
without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir* |
↓ Amprenavir ↑ Nevirapine |
No dosing adjustments are required when nevirapine is co-administered
with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination
of nevirapine administered with fosamprenavir/ritonavir once daily
has not been studied. |
| Indinavir* |
↓ Indinavir |
The appropriate doses of this combination of indinavir
and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* |
↓Lopinavir |
Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* |
↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine
and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir |
The interaction between nevirapine and
saquinavir/ritonavir has not been evaluated |
The appropriate doses of the
combination of nevirapine and saquinavir/ritonavir with respect to
safety and efficacy have not been established. |
|
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| Efavirenz* |
↓ Efavirenz |
The appropriate doses of these combinations with
respect to safety and efficacy have not been established. |
| Delavirdine Etravirine Rilpivirine |
Plasma concentrations may be altered. Nevirapine
should not be coadministered with another NNRTI as this combination
has not been shown to be beneficial. |
|
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| Boceprevir |
Plasma concentrations of boceprevir may
be decreased due to induction of CYP3A4/5 by nevirapine. |
Nevirapine and boceprevir
should not be coadministered because decreases in boceprevir plasma
concentrations may result in a reduction in efficacy. |
| Telaprevir |
Plasma concentrations of telaprevir may
be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations
of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. |
Nevirapine and telaprevir
should not be coadministered because changes in plasma concentrations
of nevirapine, telaprevir, or both may result in a reduction in telaprevir
efficacy or an increase in nevirapine-associated adverse events. |
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| Methadone* |
↓ Methadone |
Methadone levels were decreased;
increased dosages may be required to prevent symptoms of opiate withdrawal.
Methadone-maintained patients beginning nevirapine therapy should
be monitored for evidence of withdrawal and methadone dose should
be adjusted accordingly. |
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| Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have
not been established. |
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| Clarithromycin* |
↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine;
however, 14-OH metabolite concentrations were increased. Because
clarithromycin active metabolite has reduced activity against |
| Rifabutin* |
↑ Rifabutin |
Rifabutin and its metabolite concentrations were moderately increased.
Due to high intersubject variability, however, some patients may
experience large increases in rifabutin exposure and may be at higher
risk for rifabutin toxicity. Therefore, caution should be used in
concomitant administration. |
| Rifampin* |
↓ Nevirapine |
Nevirapine and rifampin should not be administered
concomitantly because decreases in nevirapine plasma concentrations
may reduce the efficacy of the drug. Physicians needing to treat
patients co-infected with tuberculosis and using a nevirapine-containing
regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
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| Fluconazole* |
↑Nevirapine |
Because of the risk of increased exposure to nevirapine, caution
should be used in concomitant administration, and patients should
be monitored closely for nevirapine-associated adverse events. |
| Ketoconazole* |
↓ Ketoconazole |
Nevirapine and ketoconazole should not be administered concomitantly
because decreases in ketoconazole plasma concentrations may reduce
the efficacy of the drug. |
| Itraconazole |
↓ Itraconazole |
Nevirapine and itraconazole should not be administered
concomitantly due to potential decreases in itraconazole plasma concentrations
that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
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||
| Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Despite lower ethinyl estradiol and norethindrone
exposures when coadministered with nevirapine, literature reports
suggest that nevirapine has no effect on pregnancy rates among HIV-infected
women on combined oral contraceptives. When coadministered with VIRAMUNE,
no dose adjustment of ethinyl estradiol or norethindrone is needed
when used in combination for contraception. When these oral contraceptives are used for hormonal regulation during VIRAMUNE therapy, the therapeutic effect of the hormonal therapy should be monitored. |
| Concomitant Drug Class: Drug Name | Effect | Clinical Comment |
|---|---|---|
|
|
||
| Protease inhibitor:
atazanavir |
↓atazanavir
↑ tenofovir |
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. |
| Protease inhibitor:
fosamprenavir calcium |
↓ amprenavir | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.
Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor:
indinavir |
↓ indinavir | The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Protease inhibitor:
lopinavir/ritonavir |
↓ lopinavir
↑ tenofovir |
Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA.
|
| Protease inhibitor:
ritonavir |
↑ ritonavir
↑ efavirenz |
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. |
| Protease inhibitor:
saquinavir |
↓ saquinavir | Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
| CCR5 co-receptor antagonist:
maraviroc |
↓ maraviroc | Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA. |
| NRTI:
didanosine |
↑ didanosine | Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information. |
| NNRTI:
Other NNRTIs |
↑ or ↓ efavirenz and/or NNRTI | Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs. |
| Integrase strand transfer inhibitor:
raltegravir |
↓ raltegravir | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
|
|
||
| Protease inhibitor:
boceprevir |
↓ boceprevir | Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided. |
| Protease inhibitor:
simeprevir |
↓ simeprevir
↔ efavirenz |
Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir. |
| NS5A inhibitor/NS5B polymerase inhibitor :
ledipasvir/sofosbuvir |
↑ tenofovir | Patients receiving ATRIPLA and HARVONI ® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF. |
|
|
||
| Anticoagulant:
warfarin |
↑ or ↓ warfarin | Plasma concentrations and effects potentially increased or decreased by efavirenz. |
| Anticonvulsants:
carbamazepine |
↓ carbamazepine
↓ efavirenz |
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. |
| phenytoin
phenobarbital |
↓ anticonvulsant
↓ efavirenz |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants:
bupropion |
↓ buproprion | The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| sertraline | ↓ sertraline | Increases in sertraline dose should be guided by clinical response. |
| Antifungals:
itraconazole |
↓ itraconazole
↓ hydroxy-itraconazole |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| ketoconazole | ↓ ketoconazole | Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. |
| posaconazole | ↓ posaconazole | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective:
clarithromycin |
↓ clarithromycin
↑ 14-OH metabolite |
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA. |
| Antimycobacterial:
rifabutin |
↓ rifabutin | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| rifampin | ↓ efavirenz | If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended. |
| Antimalarials:
artemether/lumefantrine |
↓ artemether
↓ dihydroartemisinin ↓ lumefantrine |
Artemether/lumefantrine should be used cautiously with ATRIPLA because decreased artemether, dihydroartemisinin (active metabolite of artemether), and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of artemether/lumefantrine. |
| Calcium channel blockers:
diltiazem |
↓ diltiazem
↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. |
| Others (e.g.,
felodipine, nicardipine, nifedipine, verapamil) |
↓ calcium channel blocker | No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase inhibitors:
atorvastatin pravastatin simvastatin |
↓ atorvastatin
↓ pravastatin ↓ simvastatin |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: | ||
| Oral:
ethinyl estradiol/norgestimate |
↓ active metabolites of norgestimate | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant:
etonogestrel |
↓ etonogestrel | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants:
cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immuno-suppressant | Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. |
| Narcotic analgesic:
methadone |
↓ methadone | Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Concomitant Drug Name or Drug Class | Clinical Rationale | Clinical Recommendation |
|---|---|---|
| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone
|
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage
|
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone
|
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage
|
| Antihypertensive Drugs | Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly
|
| Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone
|
Monitor sedation and blood pressure. Adjust dose accordingly. |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| * Refer to PRECAUTIONS, Drug Interactions for information regarding table. | |
| albuterol, systemic and inhaled | amoxicillin |
| ampicillin, with or without sulbactam | atenolol |
| azithromycin | caffeine, dietary ingestion |
| cefaclor | co-trimoxizole (trimethoprim and sulfamethoxazole) |
| diltiazem | dirithromycin |
| enflurane | famotidine |
| felodipine | finasteride |
| hydrocortisone | isoflurane |
| isoniazid | isradipine |
| influenza vaccine | ketoconazole |
| lomefloxacin | mebendazole |
| medroxyprogesterone | methylprednisolone |
| metronidazole | metoprolol |
| nadolol | nifedipine |
| nizatidine | norfloxacin |
| ofloxacin | omeprazole |
| prednisone, prednisolone | ranitidine |
| rifabutin | roxithromycin |
| sorbitol (purgative doses do not inhibit theophylline absorption) | sucralfate |
| terfenadine | terbutaline, systemic |
| tocainide | tetracycline |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
|---|---|
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
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| Antiarrhythmics:
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| Disopyramide
Quinidine Dofetilide Amiodarone Sotalol Procainamide |
Not Recommended |
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
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| Digoxin | Use With Caution |
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| Oral Anticoagulants:
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| Warfarin | Use With Caution |
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| Antiepileptics:
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| Carbamazepine | Use With Caution |
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| Antifungals:
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| Itraconazole | Use With Caution |
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| Fluconazole | No Dose Adjustment
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| Anti-Gout Agents:
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| Colchicine (in patients with renal or hepatic impairment)
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Contraindicated |
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| Colchicine (in patients with normal renal and hepatic function) | Use With Caution | ||||
| Antipsychotics:
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| Pimozide | Contraindicated |
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| Quetiapine |
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| Antispasmodics:
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| Tolterodine (patients deficient in CYP2D6 activity) | Use With Caution |
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| Antivirals:
|
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| Atazanavir | Use With Caution |
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| Saquinavir (in patients with decreased renal function) |
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| Ritonavir
Etravirine |
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| Maraviroc |
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| Boceprevir (in patients with normal renal function)
Didanosine |
No Dose Adjustment |
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| Zidovudine |
The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated. |
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| Calcium Channel Blockers:
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| Verapamil | Use With Caution |
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| Amlodipine
Diltiazem |
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| Nifedipine |
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| Ergot Alkaloids:
|
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| Ergotamine
Dihydroergotamine |
Contraindicated |
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| Gastroprokinetic Agents:
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| Cisapride | Contraindicated |
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| HMG-CoA Reductase Inhibitors:
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| Lovastatin
Simvastatin |
Contraindicated |
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| Atorvastatin
Pravastatin |
Use With Caution | ||||
| Fluvastatin
|
No Dose Adjustment
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| Hypoglycemic Agents:
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| Nateglinide
Pioglitazone Repaglinide Rosiglitazone |
Use With Caution |
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| Insulin |
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| Immunosuppressants:
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| Cyclosporine | Use With Caution |
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| Tacrolimus |
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| Phosphodiesterase inhibitors:
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| Sildenafil
Tadalafil Vardenafil |
Use With Caution |
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| Proton Pump Inhibitors:
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| Omeprazole | No Dose Adjustment |
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| Xanthine Derivatives:
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| Theophylline | Use With Caution |
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| Triazolobenzodiazepines and Other Related Benzodiazepines:
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| Midazolam | Use With Caution |
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| Alprazolam
Triazolam |
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
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| Temazepam
Nitrazepam Lorazepam |
No Dose Adjustment |
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| Cytochrome P450 Inducers:
|
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| Rifabutin | Use With Caution |
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| Other Drugs Metabolized by CYP3A:
|
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| Alfentanil
Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution | There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. | |||
| Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
|
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| Hexobarbital
Phenytoin Valproate |
Use With Caution | There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
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| Antifungals:
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| Itraconazole
|
Use With Caution |
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| Antivirals:
|
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| Atazanavir | Use With Caution |
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to |
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| Ritonavir (in patients with decreased renal function) |
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. |
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| Saquinavir (in patients with decreased renal function) |
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| Etravirine |
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| Saquinavir (in patients with normal renal function) | No Dose Adjustment | ||||
| Ritonavir (in patients with normal renal function)
|
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| Proton Pump Inhibitors:
|
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| Omeprazole | Use With Caution |
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| Miscellaneous Cytochrome P450 Inducers:
|
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| Efavirenz
Nevirapine Rifampicin Rifabutin Rifapentine |
Use With Caution | Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see
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| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
|---|---|
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
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Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Digoxin concentrations increased greater than 50% | |||
|---|---|---|---|
| Digoxin Serum Concentration Increase | Digoxin AUC Increase | Recommendations | |
| NA – Not available/reported | |||
| Amiodarone | 70% | NA | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring. |
| Captopril | 58% | 39% | |
| Clarithromycin | NA | 70% | |
| Dronedarone | NA | 150% | |
| Gentamicin | 129 to 212% | NA | |
| Erythromycin | 100% | NA | |
| Itraconazole | 80% | NA | |
| Lapatinib | NA | 180% | |
| Nitrendipine | 57% | 15% | |
| Propafenone | NA | 60 to 270% | |
| Quinidine | 100% | NA | |
| Ranolazine | 50% | NA | |
| Ritonavir | NA | 86% | |
| Telaprevir | 50% | 85% | |
| Tetracycline | 100% | NA | |
| Verapamil | 50 to 75% | NA | |
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| Atorvastatin | 22% | 15% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15 to 30% or by modifying the dosing frequency and continue monitoring. |
| Carvedilol | 16% | 14% | |
| Conivaptan | 33% | 43% | |
| Diltiazem | 20% | NA | |
| Indomethacin | 40% | NA | |
| Nefazodone | 27% | 15% | |
| Nifedipine | 45% | NA | |
| Propantheline | 24% | 24% | |
| Quinine | NA | 33% | |
| Raberprazole | 29% | 19% | |
| Saquinavir | 27% | 49% | |
| Spironolactone | 25% | NA | |
| Telmisartan | 20 to 49% | NA | |
| Tricagrelor | 31% | 28% | |
| Tolvaptan | 30% | NA | |
| Trimethoprim | 22 to 28% | NA | |
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| Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole | Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. | ||
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| Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John's Wort, sucralfate, sulfasalazine | Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 to 40% as necessary. | ||
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| Aspirin w/anti-inflammatory agents |
ulcerogenic effects. |
| Butalbital w/coumarin anticoagulants |
anticoagulant because of increased metabolism resulting from enzyme induction. |
| Butalbital w/tricyclic antidepressants |
levels of the antidepressant. |
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metal cations or didanosine |
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time, INR, watch for bleeding ( |
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| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents, presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
| Opioids | Cross-tolerance and mutual potentiation |
| Naltrexone | Oral THC effects were enhanced by opioid receptor blockade. |
| Alcohol | Increase in the positive subjective mood effects of smoked marijuana |
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| Concomitant Drug Class: Drug Name | Effect on Concentration of Boceprevir or Concomitant Drug | Recommendations |
|---|---|---|
| Antiarrhythmics: amiodarone, bepridil, propafenone, quinidine |
↑ antiarrhythmics |
Coadministration with VICTRELIS has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with VICTRELIS. |
| digoxin |
↑ digoxin | Digoxin concentrations increased when administered with VICTRELIS |
| Anticoagulant: warfarin | ↑ or ↓ warfarin | Concentrations of warfarin may be altered when co-administered with VICTRELIS. Monitor INR closely. |
| Antidepressants: trazodone, desipramine | ↑ trazodone ↑ desipramine |
Plasma concentrations of trazodone and desipramine may increase when administered with VICTRELIS, resulting in adverse events such as dizziness, hypotension and syncope. Use with caution and consider a lower dose of trazodone or desipramine. |
| escitalopram |
↓escitalopram | Exposure of escitalopram was slightly decreased when coadministered with VICTRELIS. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with VICTRELIS. |
| Antifungals: ketoconazole |
↑ boceprevir ↑ itraconazole ↑ ketoconazole ↑ posaconazole ↑ voriconazole |
Plasma concentrations of ketoconazole, itraconazole, voriconazole or posaconazole may be increased with VICTRELIS. When coadministration is required, doses of ketoconazole and itraconazole should not exceed 200 mg/day. |
| Anti-gout: colchicine | ↑ colchicine | Significant increases in colchicine levels are expected; fatal colchicine toxicity has been reported with other strong CYP3A4 inhibitors. Patients with renal or hepatic impairment should not be given colchicine with VICTRELIS. Treatment of gout flares (during treatment with VICTRELIS): 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares (during treatment with VICTRELIS): If the original regimen was 0.6 mg twice a day, reduce dose to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, reduce the dose to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF) (during treatment with VICTRELIS): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Anti-infective: clarithromycin | ↑ clarithromycin | Concentrations of clarithromycin may be increased with VICTRELIS; however, no dosage adjustment is necessary for patients with normal renal function. |
| Antimycobacterial: rifabutin |
↓ boceprevir ↑ rifabutin |
Increases in rifabutin exposure are anticipated, while exposure of boceprevir may be decreased. Doses have not been established for the 2 drugs when used in combination. Concomitant use is not recommended. |
| Calcium Channel Blockers such as: amlodipine, diltiazem, felodipine, nifedipine, nicardipine, nisoldipine, verapamil | ↑ calcium channel blockers | Plasma concentrations of calcium channel blockers may increase when administered with VICTRELIS. Caution is warranted and clinical monitoring is recommended. |
| Corticosteroid, systemic: dexamethasone | ↓ boceprevir | Coadministration of VICTRELIS with CYP3A4/5 inducers may decrease plasma concentrations of boceprevir, which may result in loss of therapeutic effect. Therefore, this combination should be avoided if possible and used with caution if necessary. |
| prednisone |
↑ prednisone | Concentrations of prednisone and its active metabolite, prednisolone, increased when administered with VICTRELIS |
| Corticosteroid, inhaled: budesonide, fluticasone | ↑ budesonide ↑ fluticasone |
Concomitant use of inhaled budesonide or fluticasone with VICTRELIS may result in increased plasma concentrations of budesonide or fluticasone, resulting in significantly reduced serum cortisol concentrations. Avoid coadministration if possible, particularly for extended durations. |
| Endothelin Receptor Antagonist: bosentan | ↑ bosentan | Concentrations of bosentan may be increased when coadministered with VICTRELIS. Use with caution and monitor closely. |
| HIV Integrase Inhibitor: raltegravir |
↔ raltegravir | No dose adjustment required for VICTRELIS or raltegravir. |
| HIV Non-Nucleoside Reverse Transcriptase Inhibitors: efavirenz |
↓ boceprevir | Plasma trough concentrations of boceprevir were decreased when VICTRELIS was coadministered with efavirenz, which may result in loss of therapeutic effect. Avoid combination. |
| etravirine |
↓ etravirine | Concentrations of etravirine decreased when coadministered with VICTRELIS. The clinical significance of the reductions in etravirine pharmacokinetic parameters has not been directly assessed. |
| rilpivirine |
↑ rilpivirine | Concomitant administration of rilpivirine with VICTRELIS increased the exposure to rilpivirine. No dose adjustment of VICTRELIS or rilpivirine is recommended. |
| HIV Protease Inhibitors: atazanavir/ritonavir |
↓ atazanavir ↓ ritonavir |
Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of atazanavir/ritonavir and boceprevir is not recommended. |
| darunavir/ritonavir |
↓ darunavir ↓ ritonavir ↓ boceprevir |
Concomitant administration of boceprevir and darunavir/ritonavir resulted in reduced steady-state exposures to boceprevir, darunavir and ritonavir. Coadministration of darunavir/ritonavir and boceprevir is not recommended. |
| lopinavir/ritonavir |
↓ lopinavir ↓ ritonavir ↓ boceprevir |
Concomitant administration of boceprevir and lopinavir/ritonavir resulted in reduced steady-state exposures to boceprevir, lopinavir and ritonavir. Coadministration of lopinavir/ritonavir and boceprevir is not recommended. |
| ritonavir |
↓ boceprevir | When boceprevir is administered with ritonavir alone, boceprevir concentrations are decreased. |
| HMG-CoA Reductase Inhibitors: |
|
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| atorvastatin |
↑ atorvastatin | Exposure to atorvastatin was increased when administered with VICTRELIS. Use the lowest effective dose of atorvastatin, but do not exceed a daily dose of 40 mg when coadministered with VICTRELIS. |
| pravastatin |
↑ pravastatin | Concomitant administration of pravastatin with VICTRELIS increased exposure to pravastatin. Treatment with pravastatin can be initiated at the recommended dose when coadministered with VICTRELIS. Close clinical monitoring is warranted. |
| Immunosuppressants: cyclosporine |
↑cyclosporine |
Dose adjustments of cyclosporine should be anticipated when administered with VICTRELIS and should be guided by close monitoring of cyclosporine blood concentrations, and frequent assessments of renal function and cyclosporine-related side effects. |
| tacrolimus |
↑tacrolimus |
Concomitant administration of VICTRELIS with tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects. |
| sirolimus |
↑sirolimus |
Concomitant administration of VICTRELIS with sirolimus requires significant dose reduction and prolongation of the dosing interval for sirolimus, with close monitoring of sirolimus blood concentrations and frequent assessments of renal function and sirolimus-related side effects. |
| Inhaled beta-agonist: salmeterol | ↑ salmeterol | Concurrent use of inhaled salmeterol and VICTRELIS is not recommended due to the risk of cardiovascular events associated with salmeterol. |
| Narcotic Analgesic/Opioid Dependence: methadone |
↓ |
Plasma concentrations of |
| buprenorphine/naloxone |
↑ buprenorphine/naloxone | Plasma concentrations of buprenorphine and naloxone increased when coadministered with VICTRELIS |
| Oral hormonal contraceptives: |
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| drospirenone/ethinyl estradiol |
↑ drospirenone ↓ ethinyl estradiol |
Concentrations of drospirenone increased in the presence of boceprevir. Thus, the use of drospirenone-containing products is contraindicated during treatment with VICTRELIS due to potential for hyperkalemia |
| norethindrone/ethinyl estradiol |
↓ ethinyl estradiol ↔ norethindrone |
Concentrations of ethinyl estradiol decreased in the presence of boceprevir. Norethindrone Cmax decreased 17% in the presence of boceprevir Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. |
| PDE5 inhibitors: |
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| sildenafil, tadalafil, vardenafil | ↑ sildenafil ↑ tadalafil ↑ vardenafil |
Increases in PDE5 inhibitor concentrations are expected, and may result in an increase in adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of REVATIO® (sildenafil) or ADCIRCA® (tadalafil) for the treatment of pulmonary arterial hypertension (PAH) is contraindicated with VICTRELIS Use with caution in combination with VICTRELIS with increased monitoring for PDE5 inhibitor-associated adverse events. Do not exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 24 hours |
| Proton Pump Inhibitor: omeprazole |
↔ omeprazole | No dose adjustment of omeprazole or VICTRELIS is recommended. |
| Sedative/hypnotics: |
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| alprazolam; IV midazolam | ↑ midazolam ↑ alprazolam |
Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during coadministration of VICTRELIS. A lower dose of IV midazolam or alprazolam should be considered. |
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| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with indinavir. |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA once daily in combination with nelfinavir is not recommended |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir* |
↓ lopinavir | Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended. |
| HIV CCR5 – Antagonist: maraviroc* |
↑ maraviroc | When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc. |
| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | Increase the dose of KALETRA tablets to 500/125 mg when KALETRA tablet is co-administered with efavirenz or nevirapine. KALETRA once daily in combination with efavirenz or nevirapine is not recommended |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
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| Nucleoside Reverse Transcriptase Inhibitor: tenofovir disoproxil fumarate* |
↑ tenofovir | Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
The clinical significance of this potential interaction is unknown. |
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| Antiarrhythmics e.g. amiodarone, bepridil, lidocaine (systemic), quinidine |
↑ antiarrhythmics | For contraindicated antiarrhythmics, Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib, venetoclax |
↑ anticancer agents | For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. Coadministration of venetoclax and KALETRA may increase the risk of tumor lysis syndrome. Refer to the venetoclax prescribing information for dosing instructions. |
| Anticoagulants: warfarin, rivaroxaban |
↑↓ warfarin ↑ rivaroxaban |
Concentrations of warfarin may be affected. Initial frequent monitoring of the INR during KALETRA and warfarin co-administration is recommended. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban may lead to increased risk of bleeding. |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Anticonvulsants: lamotrigine, valproate |
↓ lamotrigine ↓ or ↔ valproate |
A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, adjust clarithromycin dose as follows:
|
| Antifungals: ketoconazole*, itraconazole, voriconazole isavuconazonium sulfate* |
↑ ketoconazole ↑ itraconazole ↓ voriconazole ↑ isavuconazonium |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. The coadministration of voriconazole and KALETRA should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Isavuconazonium and Kaletra should be coadministered with caution. Alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: bedaquiline |
↑ bedaquiline | For contraindicated antimycobacterials, Bedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk. |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Antipsychotics: quetiapine | ↑ quetiapine |
Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
| Sedative/hypnotics: parenterally administered midazolam |
↑ midazolam | For contraindicated sedative/hypnotics, If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone |
↓ lopinavir ↑ glucocorticoids |
Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to lopinavir. Consider alternative corticosteroids. Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use. |
| Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Clinical monitoring of patients is recommended and a dose reduction of the dihydropyridine calcium channel blocker may be considered. |
| Disulfiram/metronidazole | KALETRA oral solution contains ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| Hepatitis C direct acting antivirals: boceprevir* simeprevir ombitasvir/paritaprevir/ ritonavir and dasabuvir* |
↓ lopinavir ↓ boceprevir ↓ ritonavir ↑ simeprevir ↑ ombitasvir ↑ paritaprevir ↑ ritonavir ↔ dasabuvir |
For contraindicated hepatitis C direct acting antivirals, It is not recommended to co-administer KALETRA and boceprevir, simeprevir, or ombitasvir/paritaprevir/ritonavir and dasabuvir. |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
For contraindicated HMG-CoA reductase inhibitors, Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. |
| Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Long-acting beta-adrenoceptor Agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesics: methadone,* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil |
↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil |
For contraindicated PDE5 inhibitors, Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
| * |
||
| Classes of Drugs | |||
| 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials |
Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors† |
Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins† |
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? carbamazepine epoxide |
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? valproate |
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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ |
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During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil |
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dofetilide, dronedarone, quinidine |
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cilostazol, dabigatran |
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saxagliptin |
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ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine) |
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dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib |
busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids |
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oral midazolam, pimozide, triazolam |
aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone |
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indinavir, ritonavir, |
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nisoldipine |
verapamil |
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sildenafil, for the treatment of pulmonary hypertension |
riociguat |
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temsirolimus |
ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus |
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simvastatin |
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vardenafil |
oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine |
Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation. |
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conivaptan, tolvaptan |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
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| Grapefruit juice | Avoid grapefruit juice |
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The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice |
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The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase |
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If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression. |
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Rifampin, carbamazepine, phenytoin |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome |
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The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs. |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 50 mg (95% CI) |
| Supine | 9.08 (5.48, 12.68) |
| Standing |
11.62 (7.34, 15.90) |
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(Cmax and AUC |
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Efavirenz (300 mg q24h)** (CYP450 Induction) |
Slight Decrease in AUCτ |
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Reduced |
Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
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indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
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Careful assessment of voriconazole effectiveness |
| Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements. | |
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| Phenobarbital
Rifampin |
Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine. |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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| Concomitant Drug
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Effect onConcentration ofLamotrigine orConcomitant Drug
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Clinical Comment
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| Estrogen-containing oralcontraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine
↓ levonorgestrel |
Decreased lamotrigine concentrationsapproximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepineand carbamazepine epoxide
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↓ lamotrigine
? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentrationapproximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUCapproximately 32%. |
| Phenobarbital/primidone
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↓ lamotrigine
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Decreased lamotrigine concentration approximately 40%. |
| Phenytoin
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↓ lamotrigine
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Decreased lamotrigine concentration approximately 40%. |
| Rifampin
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↓ lamotrigine
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Decreased lamotrigine AUC approximately 40%. |
| Valproate
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↑ lamotrigine
? valproate |
Increased lamotrigine concentrations slightly more than 2-fold.There are conflicting study resultsregarding effect of lamotrigine onvalproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change invalproate concentrations in controlled clinical trials in patients with epilepsy. |
| Oral hypoglycemics | Tofacitinib | Cyclophosphamide |
| Coumarin-type anticoagulants | Triazolam | Fentanyl |
| Phenytoin | Oral contraceptives | Halofantrine |
| Cyclosporine | Pimozide | HMG-CoA reductase inhibitors |
| Rifampin | Quinidine | Losartan |
| Theophylline | Hydrochlorothiazide | Methadone |
| Terfenadine | Alfentanil | Non-steroidal anti-inflammatory drugs |
| Cisapride | Amitriptyline, nortriptyline | Prednisone |
| Astemizole | Amphotericin B | Saquinavir |
| Rifabutin | Azithromycin | Sirolimus |
| Voriconazole | Carbamazepine | Vinca alkaloids |
| Tacrolimus | Calcium channel blockers | Vitamin A |
| Short-acting benzodiazepines | Celecoxib | Zidovudine |
| Classes of Drugs | |||
|---|---|---|---|
| 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials |
Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors† |
Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins† |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| ↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change | ||||||
| QD-once daily; BID-twice daily; TID – thrice daily | ||||||
| ND -No Data | ||||||
| AUC -Area under the Concentration vs. Time Curve; C max -Maximum serum concentration | ||||||
| a compared to rifabutin 300 mg QD alone | ||||||
| b compared to historical control (fosamprenavir/ritonavir 700/100 mg BID) | ||||||
| c also taking zidovudine 500 mg QD | ||||||
| d compared to rifabutin 150 mg QD alone | ||||||
| e compared to rifabutin 300 mg QD alone | ||||||
| f data from a case report | ||||||
| g compared to voriconazole 200 mg BID alone | ||||||
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drug |
of coadministered drug |
regimen of rifabutin |
population (n) |
rifabutin |
coadministered drug |
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10 days |
x 10 days |
subjects (6) |
↑ C max by 119% |
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50%. Monitor closely for adverse reactions. |
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patients (7) |
↑ C max by 128% |
↓ Cmax by 75%, ↓ C min by 17% |
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x 12 days |
mg QD x 1 |
patients (11) |
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ritonavir |
ritonavir 100 mg BID x 2 weeks |
every other day x 2 weeks |
subjects (15) |
↓ C max by 15% |
↑ C max by 36%, ↑ C min by 36% |
75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ ritonavir combination. |
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x 10 days |
x 10 days |
subjects (10) |
↑ C max by 134% |
↓ C max by 25%, ↓ C min by 39% |
increase indinavir dose from 800 mg to 1000 mg TID. |
|
ritonavir |
x 20 days |
x 10 days |
subjects (14) |
↓ C max by 112% |
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75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
|
ritonavir |
x 14 or 22 days |
3 days X 21 to 22 days |
subjects |
↑ C max by 88% (n=11) |
↓ C max by 15%, (n=19) |
75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions. |
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x 10 days |
x 16 days |
subjects (5) |
↑ C max by 150% |
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75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
|
ritonavir |
X 15 doses |
single dose |
subjects (20) |
↑ C max by 70% |
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75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
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x 7 to 8 days |
x 8 days |
patients (11) |
↑ C max by 19% |
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(to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID |
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q4h |
mg QD |
patients (16) |
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↓ C max by 48% |
within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary. |
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x 2 weeks |
x 2 weeks |
patients (12) |
↑C max by 88% |
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adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected. |
|
|
x 10 days |
x 17 days |
subjects (8) |
↑ C max by 31% |
↓ C max by 43% |
drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy. |
|
|
|
|
patients (6) |
|
↓ C max by 75% |
drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following coadministration of rifabutin (300 mg QD) with itraconazole (600 to 900 mg QD). |
|
|
x 7 days (maintenance dose) |
x 7 days |
subjects (12) |
↑ C max by 195% |
↑ C max by ~100% g |
|
|
|
||||||
|
|
|
|
patients (16) |
|
|
|
|
-Trimethoprim |
|
|
patients (12) |
|
|
|
|
|
||||||
|
|
x 1 day, then 250 mg QD x 9 days |
|
subjects (6) |
|
|
|
|
|
|
|
patients (12) |
|
|
adverse events. Reduce dose or suspend use of rifabutin if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin |
|
|
||||||
|
|
|
X 7 days |
subjects(10) |
|
|
|
|
|
|
X 7 days |
subjects (6) |
|
|
|
|
|
||||||
|
|
mg QD |
X 13 days |
patients (24) |
|
|
|
|
Norethindrone (NE) |
1 mg NE X 21 days |
X 10 days |
subjects (22) |
|
↓ C max by 20% NE: ↓ AUC by 46% |
additional or alternative methods of contraception. |
|
|
|
X 14 days |
subjects (11) |
|
|
|
| *Change relative to reference
|
|||||
| Coadministered Drug
|
Dosing Schedule
|
Effect on Active Moiety
(Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose
Recommendation |
||
| Coadministered Drug
|
Risperidone
|
AUC
|
C
max
|
||
| Enzyme (CYP2D6) inhibitors
|
|
|
|
|
|
| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice daily
|
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
-
|
Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day
|
4 mg/day
|
1.6
|
-
|
||
| 40 mg/day
|
4 mg/day
|
1.8
|
-
|
||
| Enzyme (CYP3A/ PgP inducers) Inducers
|
|
|
|
|
|
| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) inhibitors
|
|
|
|
|
|
| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not needed
|
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not needed
|
| Erythromycin
|
500 mg four times daily
|
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not needed
|
| Other Drugs
|
|
|
|
|
|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not Needed
|
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
|
| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
| Drug | Description |
|---|---|
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia |
| Uricosuric Agents | Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited |
|
|
|
| Known CYP2D6 Poor Metabolizers
|
Administer half of usual dose
|
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
|
Administer a quarter of usual dose
|
| Strong CYP2D6 or CYP3A4 inhibitors
|
Administer half of usual dose
|
| Strong CYP2D6 and CYP3A4 inhibitors
|
Administer a quarter of usual dose
|
| Strong CYP3A4 inducers
|
Double usual dose over 1 to 2 weeks
|
|
|
|
|
| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
|
|
? carbamazepine epoxide |
May increase carbamazepine epoxide levels. |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
? valproate |
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
|
|
|
|
|---|---|---|
| nafcillin rifampin |
carbamazepine oxcarbazepine phenobarbital phenytoin |
bosentan octreotide orlistat sulfinpyrazone St. John's Wort terbinafine ticlopidine |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
|
|
| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
| a Should be administered at least 4 hours prior to WELCHOL | |
|
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an |
|
|
|
|
| d Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs. | |
|
|
|
| Drugs with a known interaction with colesevelam: Decrease in exposure of coadministered drug |
cyclosporinec, glimepiridea, glipizidea, glyburidea, levothyroxinea, olmesartan medoxomila, and oral contraceptives containing ethinyl estradiol and norethindronea |
| Drugs with a known interaction with colesevelam: Increase in exposure of coadministered drug |
metformin extended release (ER)d |
| Drug(s) with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL |
phenytoina, warfarinb |
| Drugs that do not interact with colesevelam based on |
aspirin, atenolol, cephalexin, ciprofloxacin, digoxin, enalapril, fenofibrate, lovastatin, metformin, metoprolol, phenytoina, pioglitazone, rosiglitazone, quinidine, repaglinide, sitagliptin, valproic acid, verapamil, warfarinb |
|
|
|
|
e.g., |
|
|
e.g., tri-iodothyronine |
2 weeks |
|
|
2 weeks |
|
|
|
|
|
|
|
corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium |
1 week 1 week 1-2 weeks 4 weeks |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Norepinephrine Dopamine |
|
|
|
|
|
|
|
|
|
|
|
|
|
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents | Carefully monitor blood glucose |
|
* Results based on ** Results based on *** Results based on **** Non-Steroidal Anti-Inflammatory Drug ***** Non-Nucleoside Reverse Transcriptase Inhibitors |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
(Mechanism of Interaction by Voriconazole) |
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sirolimus* (CYP3A4 Inhibition) |
Significantly Increased |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Rifabutin* (CYP3A4 Inhibition) |
Significantly Increased |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Efavirenz (400 mg q24h)** (CYP3A4 Inhibition) Efavirenz (300 mg q24h)** (CYP3A4 Inhibition) |
Significantly Increased Slight Increase in |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| High-dose Ritonavir (400 mg q12h)** (CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)** |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ
Slight Decrease in Ritonavir Cmax and AUCτ |
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cyclosporine* (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax
|
When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Methadone*** (CYP3A4 Inhibition) |
Increased |
Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Fentanyl (CYP3A4 Inhibition) |
Increased |
Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alfentanil (CYP3A4 Inhibition) |
Significantly Increased |
Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablet. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Oxycodone (CYP3A4 Inhibition) |
Significantly Increased |
Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition) |
Increased |
Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Tacrolimus* (CYP3A4 Inhibition) |
Significantly Increased |
When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenytoin* (CYP2C9 Inhibition) |
Significantly Increased |
Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** |
Increased |
Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Warfarin* (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased |
Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Omeprazole* (CYP2C19/3A4 Inhibition) |
Significantly Increased |
When initiating therapy with voriconazole |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment for indinavir when coadministered with voriconazole tablets Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other NNRTIs***** (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Benzodiazepines (CYP3A4 Inhibition) |
|
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
|
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
|
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Everolimus (CYP3A4 Inhibition) |
Not Studied |
Concomitant administration of voriconazole and everolimus is not recommended. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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||
| Atazanavir/Ritonavir* |
↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* |
↓Amprenavir ↑Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir* |
↓Amprenavir ↑Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* |
↓ Indinavir |
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* |
↓Lopinavir |
Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* |
↓ Nelfinavir M8 Metabolite ↓ Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir |
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated |
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
|
||
| Efavirenz* |
↓ Efavirenz |
The appropriate doses of these combinations with respect to safety and efficacy have not been established. |
| Delavirdine Etravirine Rilpivirine |
|
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
|
|
||
| Boceprevir |
Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. |
Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy. |
| Telaprevir |
Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. |
Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events. |
|
|
||
|
Methadone* |
↓Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Clarithromycin* |
↓Clarithromycin ↑14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Rifabutin* |
↑Rifabutin |
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin* |
↓Nevirapine |
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* |
↑Nevirapine |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Ketoconazole* |
↓Ketoconazole |
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Itraconazole |
↓Itraconazole |
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓Ethinyl estradiol ↓Norethindrone |
Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception. When these oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored. |
| * The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. |
||
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| nafcillin | carbamazepine | bosentan | terbinafine |
| rifampin | oxcarbazepine | octreotide | ticlopidine |
| phenobarbital | orlistat | St. John's Wort | |
| phenytoin | sulfinpyrazone | ||
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| DRUG | DESCRIPTION OF INTERACTION |
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. |
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. |
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| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol, verapamil, diltiazem |
Contraindicated with SIMCOR |
| Amiodarone, amlodipine, ranolazine | Do not exceed 1000/20 mg SIMCOR daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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The concomitant use of tramadol hydrochloride and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression |
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If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation. |
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Quinidine, fluoxetine, paroxetine and bupropion |
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The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease |
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|
If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) |
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The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase |
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If concomitant use is necessary, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride and acetaminophen and carbamazepine is not recommended. |
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Rifampin, carbamazepine, phenytoin |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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|
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride and acetaminophen if serotonin syndrome is suspected. |
|
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome |
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Do not use tramadol hydrochloride and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of tramadol hydrochloride and acetaminophen and/or precipitate withdrawal symptoms. |
|
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride and acetaminophen and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
|
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Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride and acetaminophen is used concomitantly with anticholinergic drugs. |
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Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity. |
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Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed. |
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Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times. |
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Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed. |
| Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. | |
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| Beta-adrenergic antagonists (e.g., Propranolol > 160 mg/day) |
In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state. |
| Glucocorticoids (e.g., Dexamethasone |
Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above). |
| Other drugs: Amiodarone |
Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients. |
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| nafcillin | carbamazepine | bosentan | St. John’s Wort |
| rifampin | oxcarbazepine | octreotide | |
| phenobarbital | orlistat | ||
| phenytoin | sulfinpyrazone | ||
| terbinafine | |||
| ticlopidine | |||
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole tablets with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole tablets alone |
Withconcomitant use of aripiprazole tablets with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole tablets dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole tablets and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole tablets alone |
Withconcomitant use of aripiprazole tablets with a strong CYP3A4 inducer, consider increasing the aripiprazole tablets dosage |
| AntihypertensiveDrugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor bloodpressure and adjust dose accordingly |
| Benzodiazepines(e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
| AED Coadministered |
AED Concentration |
Topiramate Concentration |
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||
| Phenytoin |
NC or 25% increasea |
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb |
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole. |
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Dose adjustment of paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor. |
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Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol. |
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Recommend to take paricalcitol capsules at least 1 hour |
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Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol. |
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Recommend to take paricalcitol capsules at least 1 hour |
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| Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide |
Recommended |
occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
| Digoxin | Use With Caution |
|
| Oral Anticoagulants: Warfarin |
Use With Caution |
|
| Antiepileptics: Carbamazepine |
Use With Caution |
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Colchicine (in patients with renal or hepatic impairment) with normal renal and hepatic function) |
|
CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function |
| Antipsychotics: Pimozide Quetiapine |
Contraindicated |
|
| Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity) |
Use With Caution |
|
| Antivirals: |
|
|
| Calcium Channel Blockers: Verapamil |
Use With Caution |
|
| Ergot Alkaloids: Ergotamine Dihydroergotamine |
Contraindicated |
reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system |
|
Agents: |
Contraindicated |
|
| HMG-CoA Reductase Inhibitors: Simvastatin Pravastatin |
|
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| Hypoglycemic Agents: Pioglitazone Repaglinide Rosiglitazone Insulin |
Use With Caution |
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|
Use With Caution |
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Tadalafil Vardenafil |
Use With Caution |
|
| Proton Pump Inhibitors: Omeprazole |
No Dose Adjustment |
|
| Xanthine Derivatives: Theophylline |
Use With Caution |
|
|
Nitrazepam Lorazepam |
|
|
| Cytochrome P450 Inducers: Rifabutin | Use With Caution |
|
| Other Drugs Metabolized by CYP3A: Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution | There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. |
| Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate |
Use With Caution | There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. |
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| Antifungals: Itraconazole |
Use With Caution |
|
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Atazanavir |
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|
| Proton Pump Inhibitors: |
Use With Caution |
|
| Miscellaneous Cytochrome P450 Inducers: Nevirapine Rifampicin Rifabutin Rifapentine |
Use With Caution | Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above). |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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| CYP2C9
|
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
|
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
|
| CYP1A2
|
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
|
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
|
| CYP3A4
|
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
|
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide
|
| Interacting Drug | Interaction |
|---|---|
| Drugs known to prolong QT interval (e.g., Class IA and Class III anti-arrhythmic agents). | Quinine Sulfate Capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use ( |
| Other antimalarials (e.g., halofantrine, mefloquine). | ECG abnormalities including QT prolongation. Avoid concomitant use ( |
| CYP3A4 inducers or inhibitors | Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( |
| CYP3A4 and CYP2D6 substrates | Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( |
| Digoxin | Increased digoxin plasma concentration ( |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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Hepatitis C protease inhibitor (boceprevir) |
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| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose |
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| Multivalent cation-containing products including antacids,
metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (
|
| Warfarin
|
Effect may be enhanced. Monitor prothrombin
time, INR, watch for bleeding ( |
| Antidiabetic agents
|
Carefully monitor blood glucose (
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Known CYP2D6 Poor Metabolizers |
Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors |
Administer a quarter of usual dose |
| Strong CYP2D6 |
Administer half of usual dose |
| Strong CYP2D6 inhibitors |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers |
Double usual dose over 1 to 2 weeks |
| Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Voriconazole Tofacitinib Oral Contraceptives Hydrochlorothiazide Amitriptyline, nortriptyline Azithromycin Calcium Channel Blockers Cyclophosphamide |
Quinidine Halofantrine Losartan Non-steroidal anti-inflammatory drugs Saquinavir Vinca Alkaloids Zidovudine Terfenadine Cisapride Astemizole Rifabutin Tacrolimus Short-acting benzodiazepines |
Triazolam Pimozide Alfentanil Amphotericin B Carbamazepine Celecoxib Fentanyl HMG-CoA reductase inhibitors Methadone Prednisone Sirolimus Vitamin A |
| NA - Not available/reported | |||
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| Digoxin Serum Concentration Increase | Digoxin AUC Increase | Recommendations | |
| Amiodarone | 70% | NA | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring. |
| Captopril | 58% | 39% | |
| Nitrendipine | 57% | 15% | |
| Propafenone | 35-85% | NA | |
| Quinidine | 100% | NA | |
| Ranolazine | 87% | 88% | |
| Ritonavir | NA | 86% | |
| Verapamil | 50-75% | NA | |
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| Carvedilol | 16% | 14% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring. |
| Diltiazem | 20% | NA | |
| Nifedipine | 45% | NA | |
| Rabeprazole | 29% | 19% | |
| Telmisartan | 20% | NA | |
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| Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline | Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. | ||
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| Acarbose, Activated Charcoal, Albuterol, Antacids, Anticancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclpramide, Miglitol, Neomycin, Rifampin, Salbutamol, St.John's Wort, Sucralfate, Sulfasalazine | Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary. | ||
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| Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. | No additional actions are required. | ||
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Phenytoin Phenobarbital St. John’s wort ( |
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Sucralfate Buffered medications |
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| Concomitant Drug Class: Drug Name | Effect | Clinical Comment |
|---|---|---|
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||
| Protease inhibitor: atazanavir |
↓atazanavir concentration ↑ tenofovir concentration |
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. |
| Protease inhibitor: fosamprenavir calcium |
↓ amprenavir concentration | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: indinavir |
↓ indinavir concentration | The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Protease inhibitor: lopinavir/ritonavir |
↓ lopinavir concentration ↑ tenofovir concentration |
A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). |
| Protease inhibitor: ritonavir |
↑ ritonavir concentration ↑ efavirenz concentration |
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. |
| Protease inhibitor: saquinavir |
↓ saquinavir concentration | Should not be used as sole protease inhibitor in combination with ATRIPLA. |
| CCR5 co-receptor antagonist: maraviroc |
↓ maraviroc concentration | Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA. |
| NRTI: didanosine |
↑ didanosine concentration | Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. |
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||
| Anticoagulant: warfarin |
↑ or ↓ warfarin concentration | Plasma concentrations and effects potentially increased or decreased by efavirenz. |
| Anticonvulsants: carbamazepine |
↓ carbamazepine concentration ↓ efavirenz concentration |
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. |
| phenytoin phenobarbital |
↓ anticonvulsant concentration ↓ efavirenz concentration |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants: bupropion |
↓ buproprion concentration | The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| sertraline | ↓ sertraline concentration | Increases in sertraline dose should be guided by clinical response. |
| Antifungals: itraconazole |
↓ itraconazole concentration ↓ hydroxy-itraconazole concentration |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| ketoconazole | ↓ ketoconazole concentration | Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. |
| posaconazole | ↓ posaconazole concentration | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective: clarithromycin |
↓ clarithromycin concentration ↑ 14-OH metabolite concentration |
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA. |
| Antimycobacterial: rifabutin |
↓ rifabutin concentration | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| Antimycobacterial: rifampin |
↓ efavirenz concentration | If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended. |
| Calcium channel blockers: diltiazem |
↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. |
| Others (e.g., felodipine, nicardipine, nifedipine, verapamil) |
↓ calcium channel blocker | No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin |
↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: | ||
| Oral: ethinyl estradiol/norgestimate |
↓ active metabolites of norgestimate | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant: etonogestrel |
↓ etonogestrel | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immuno-suppressant | Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. |
| Narcotic analgesic: methadone |
↓ methadone concentration | Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
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| Dopamine/Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone
Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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|
|||
|
|
|
||
| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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Efavirenz (300 mg q24h)** |
Slight Increase in AUCτ |
When voriconazole is coadministered with efavirenz, voriconazole oral |
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AUCτ |
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(CYP3A4 Inhibition) |
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| Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. | |
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| Calcium Carbonate Ferrous Sulfate |
Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents. |
| Orlistat | Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function. |
| Bile Acid Sequestrants - Colesevelam - Cholestyramine - Colestipol Ion Exchange Resins - Kayexalate - Sevelamer |
Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels. |
| Other drugs: Proton Pump Inhibitors Sucralfate Antacids - Aluminum & Magnesium Hydroxides - Simethicone |
Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately. |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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| Concomitant Drug Class: Drug Name | Effect | Clinical Comment |
|---|---|---|
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| Protease inhibitor: atazanavir |
↓atazanavir ↑ tenofovir |
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. |
| Protease inhibitor: fosamprenavir calcium |
↓ amprenavir | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: indinavir |
↓ indinavir | The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Protease inhibitor: lopinavir/ritonavir |
↓ lopinavir ↑ tenofovir |
Do not use once daily administration of lopinavir/ritonavir. Dose adjustment of lopinavir/ritonavir is recommended when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions. |
| Protease inhibitor: ritonavir |
↑ ritonavir ↑ efavirenz |
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. |
| Protease inhibitor: saquinavir |
↓ saquinavir | Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
| CCR5 co-receptor antagonist: maraviroc |
↓ maraviroc | Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA. |
| NRTI: didanosine |
↑ didanosine | Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when co-administered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information. |
| NNRTI: Other NNRTIs |
↑ or ↓ efavirenz and/or NNRTI | Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs. |
| Integrase strand transfer inhibitor: raltegravir |
↓ raltegravir | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
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| Protease inhibitor: boceprevir |
↓ boceprevir | Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided. |
| Protease inhibitor: telaprevir |
↓ telaprevir ↓ efavirenz |
Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz. |
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| Anticoagulant: warfarin |
↑ or ↓ warfarin | Plasma concentrations and effects potentially increased or decreased by efavirenz. |
| Anticonvulsants: carbamazepine |
↓ carbamazepine ↓ efavirenz |
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. |
| phenytoin phenobarbital |
↓ anticonvulsant ↓ efavirenz |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants: bupropion |
↓ buproprion | The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| sertraline | ↓ sertraline | Increases in sertraline dose should be guided by clinical response. |
| Antifungals: itraconazole |
↓ itraconazole ↓ hydroxy-itraconazole |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| ketoconazole | ↓ ketoconazole | Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. |
| posaconazole | ↓ posaconazole | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective: clarithromycin |
↓ clarithromycin ↑ 14-OH metabolite |
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA. |
| Antimycobacterial: rifabutin |
↓ rifabutin concentration | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| rifampin | ↓ efavirenz | If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended. |
| Calcium channel blockers: diltiazem |
↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. |
| Others (e.g., felodipine, nicardipine, nifedipine, verapamil) |
↓ calcium channel blocker | No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin |
↓ atorvastatin ↓ pravastatin ↓ simvastatin |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: | ||
| Oral: ethinyl estradiol/norgestimate |
↓ active metabolites of norgestimate | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant: etonogestrel |
↓ etonogestrel | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immuno-suppressant | Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. |
| Narcotic analgesic: methadone |
↓ methadone | Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
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| Grapefruit juice | Avoid grapefruit juice |
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↑ Nevirapine |
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↑ Nevirapine |
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↑ Nevirapine |
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↓ Nelfinavir Cmin |
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Etravirine Rilpivirine |
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↓ Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
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↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
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Carbamazepine, clonazepam, ethosuximide |
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Fluconazole |
↑ Nevirapine |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
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Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
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Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
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Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
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Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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Ethinyl estradiol and Norethindrone |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
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• Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity • There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole. |
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mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. |
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Amoxicillin also has drug interactions. |
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a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. |
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b = Is not administered but is an active metabolite of carbamazepine. |
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| NC = Less than 10% change in plasma concentration. |
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| NE = Not Evaluated |
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| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing of these drugs for use in patients
for whom alternative treatment options are inadequate. Limit dosages
and durations to the minimum required. Follow patients closely for
signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DILAUDID Oral Solution or DILAUDID Tablets if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome
or opioid toxicity (e.g., respiratory depression, coma) If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. |
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The use of DILAUDID Oral Solution or DILAUDID Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of DILAUDID Oral Solution or DILAUDID Tablets and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine, |
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Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DILAUDID Oral Solution or DILAUDID Tablets and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when DILAUDID Oral Solution or DILAUDID Tablets is used concomitantly with anticholinergic drugs. |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) | Do not exceed 40 mg atorvastatin daily |
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| Multivalent cation-containing
products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (
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| Warfarin
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Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
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| Antidibetic agents
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Carefully monitor blood glucose (
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| *Refer to |
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| albuterol, systemic and inhaled | felodipinefinasteride | nizatidinenorfloxacin | |
| amoxicillin | hydrocortisone | ofloxacin | |
| ampicillin, with or without sulbactam | isoflurane isoniazid | omeprazole prednisone, prednisolone | |
| atenolol | isradipine | ranitidine | |
| azithromycin | influenza vaccine | rifabutin | |
| caffeine, dietary ingestion | ketoconazo lelomefloxacin | roxithromycin sorbitol | |
| cefaclor | mebendazole | (purgative doses do not | |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | medroxyprogesteronemethylprednisolone | inhibit theophylline absorption) | |
| diltiazem | metronidazole | sucralfate | |
| dirithromycin | metoprolol | terbutaline, systemic | |
| enflurane | nadolol | terfenadine | |
| famotidine | nifedipine | tetracycline | |
| tocainide | |||
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
|
Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40% May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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Tipranavir/ritonavira |
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Phenytoin Phenobarbital St. John’s wort ( |
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Sucralfate Buffered medications |
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| Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with VYTORIN |
| Verapamil, diltiazem | Do not exceed 10/10 mg VYTORIN daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 10/20 mg VYTORIN daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Classes of Drugs | ||
| Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics† |
Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics† |
Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins† |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| a Total estrogens is the sum of conjugated and unconjugated estrogen. | ||||||
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| Estradiol | 0.037 ± 0.048 |
12.7 ± 9.1 |
0.676 ± 0.737 |
0.030 ± 0.032 |
17.32 ± 1.21 |
0.561 ± 0.572 |
| Estrone Total a |
3.68 ± 1.55 |
10.6 ± 6.8 |
61.3 ± 26.36 |
4.93 ± 2.07 |
7.5 ± 3.8 |
85.9 ± 41.2 |
| Equilin Total a |
2.27 ± 0.95 |
6.0 ± 4.0 |
28.8 ± 13.0 |
3.22 ± 1.13 |
5.3 ± 2.6 |
38.1 ± 20.2 |
| Interacting Drug | Interaction |
|---|---|
| Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). | QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use ( |
| Other antimalarials (e.g., halofantrine, mefloquine). | ECG abnormalities including QT prolongation. Avoid concomitant use ( |
| CYP3A4 inducers or inhibitors | Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( |
| CYP3A4 and CYP2D6 substrates | Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( |
| Digoxin | Increased digoxin plasma concentration ( |
| |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
|
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
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With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. | Monitor blood pressure and adjust dose accordingly |
| |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) | The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) | The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs | Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. | Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines (e.g., lorazepam) | The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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Decreased exposure of omeprazole when used concomitantly with strong inducers |
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Increased exposure of omeprazole |
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albuterol, systemic and inhaled |
mebendazole |
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amoxicillin |
medroxyprogesterone |
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ampicillin, with or without |
methylprednisolone |
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sulbactam |
metronidazole |
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atenolol |
metoprolol |
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azithromycin |
nadolol |
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caffeine, dietary ingestion |
nifedipine |
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cefaclor |
nizatidine |
|
co-trimoxazole (trimethoprim and sulfamethoxazole) |
norfloxacin |
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ofloxacin |
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diltiazem |
omeprazole |
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dirithromycin |
prednisone, prednisolone |
|
enflurane |
ranitidine |
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famotidine |
rifabutin |
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felodipine |
roxithromycin |
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finasteride |
Sorbitol (purgative doses do not inhibit |
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hydrocortisone |
theophylline absorption) |
|
isoflurane |
sucralfate |
|
isoniazid |
terbutaline, systemic |
|
isradipine |
terfenadine |
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influenza vaccine |
tetracycline |
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ketoconazole |
tocainide |
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lomefloxacin |
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Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib capsules have no effect on methotrexate pharmacokinetics. |
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During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [ |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [ |
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Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see |
| DRUG | DISCRIPTION OF INTERACTION |
|---|---|
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. |
| Acidifying agents | Increases plasma salicylate levels. |
| Alkcanizing agents | Decreased plasma salicylate levels. |
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| Clinical Impact: | Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. | |
| Intervention: |
Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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| Clinical Impact: |
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
|
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| Intervention: |
Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
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| Clinical Impact: | NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. | |
| Intervention: |
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [
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| Clinical Impact: |
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [
|
|
| Intervention: |
Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [
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| Clinical Impact: | The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. | |
| Intervention: | During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. | |
|
|
||
| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. | |
| Intervention: | During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. | |
|
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||
| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). | |
| Intervention: | During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity. | |
| Intervention: | During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. | |
|
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| Clinical Impact: |
Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
|
|
| Intervention: | The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). | |
| Intervention: | During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. | |
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| Clinical Impact: | When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. | |
| Intervention: | During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. | |
| a 400 mg of lopinavir in combination with 100 mg of ritonavir. | ||
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| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate |
| Drugs Known to Prolong QT Interval |
Avoid Use | Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin. |
| Cyclosporine | Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine. |
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin |
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised. |
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil | Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine | Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
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| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Probenecid | Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
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The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice |
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The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase |
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If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression. |
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Rifampin, carbamazepine, phenytoin |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome |
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The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs. |
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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See |
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio
|
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| AED Coadministered | Dose of AED (mg/day) |
Oxcarbazepine Tablets Dose (mg/day) |
Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval) |
Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc |
40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc up to 40% increase [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc |
18% decrease [CI: 13% decrease, 40% decrease] |
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| Phenytoin
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NCor25%increase
a
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48%decrease
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| Carbamazepine(CBZ)
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NC
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40%decrease
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| CBZepoxide
b
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NC
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NE
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| Valproic acid
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11%decrease
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14%decrease
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| Phenobarbital
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NC
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NE
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| Primidone
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NC
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NE
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| Lamotrigine
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NCatTPM dosesupto400 mg/day
|
13%decrease
|
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Coadministered Drugs | Effect on Rifabutin | Effect on Coadministered Drug | Comments |
|---|---|---|---|
| ANTIVIRALS | |||
| Amprenavir | 2.9-fold ↑ AUC, 2.2-fold ↑ Cmax | No significant change in kinetics. | A 50% reduction in the rifabutin dose is recommended when combined with amprenavir. Increased monitoring for adverse reactions is warranted. |
| Delavirdine | ND | Oral clearance ↑ 5-fold resulting in significantly lower mean trough plasma concentrations (18±15 to 1.0±0.7 µM) | Study conducted in HIV-1 infected patients Rifabutin is not recommended for patients dosed with delavirdine mesylate 400 mg q8h. |
| Didanosine | No significant change in kinetics. | No significant change in kinetics at steady state. | |
| Fosamprenavir/ritonavir | 64% ↑ AUC |
35% ↑ AUC and 36% ↑ Cmax, no effect Ctrough (amprenavir) | Dosage reduction of rifabutin by at least 75% (to 150 mg every other day or three times per week) is recommended when combined with fosamprenavir |
| Indinavir | 204% ↑ in AUC | 32%↓ in AUC | |
| Lopinavir/ritonavir | 5.7-fold ↑ AUC, 3.4 fold ↑ Cmax |
No significant change in lopinavir kinetics. | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted. Further dosage reduction of rifabutin may be necessary. |
| Saquinavir | ND | 40% ↓ in AUC | |
| Ritonavir | 4 fold increase in AUC, 2.5 fold increase in Cmax | ND | In the presence of ritonavir the subsequent risk of side effects, including uveitis may be increased . If a protease inhibitor is required in a patient treated with rifabutin, agents other than ritonavir should be considered. |
| Tipranavir/ritonavir[133] | 2.9-fold ↑ AUC, 1.7-fold ↑ Cmax | No significant change in tipranavir kinetics. | Therapeutic drug monitoring of rifabutin is recommended. |
| Zidovudine | No significant change in kinetics. | Approximately 32%↓ in Cmax and AUC | A large controlled clinical study has shown that these changes are of no clinical relevance. |
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| ANTIFUNGALS | 82% ↑ in AUC | No significant change in steady-state plasma concentrations | |
| Itraconazole | ND | 70% to 75% ↓ in Cmax and AUC | One case report suggests a kinetic interaction resulting in an increase in serum rifabutin levels and a risk for developing uveitis in the presence of itraconazole. |
| Posaconazole | 31%↑ Cmax, 72%↑ AUC | 43%↓ Cmax, 49%↓ AUC | If the drugs are co-administered, patients should be monitored for adverse events associated with rifabutin administration. |
| Voriconazole | 195%↑ Cmax, 331%↑ AUC |
Rifabutin (300 mg once daily) decreased the Cmax and AUC of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During co-administration with rifabutin, the Cmax and AUC of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily Cmax and AUC were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily. | If the benefit outweighs the risk, rifabutin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours or from 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole |
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| Dapsone | ND | Approximately 27% to 40% ↓ in AUC | Study conducted in HIV infected patients (rapid and slow acetylators). |
| Sulfamethoxazole-Trimethoprim | No significant change in Cmax and AUC | Approximately 15% to 20% ↓ in AUC | In another study, only trimethoprim (not sulfamethoxazole) had 14% ↓ in AUC and 6%↓ in Cmax but were not considered clinically significant. |
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| Azithromycin | No PK interaction | No PK interaction | |
| Clarithromycin | Approximately 77% ↑ in AUC | Approximately 50%↓ in AUC | Study conducted in HIV infected patients. Dose of rifabutin should be adjusted in the presence of clarithromycin |
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| Ethambutol | ND | No significant change in AUC or Cmax | |
| Isoniazid | ND | Pharmacokinetics not affected | |
| Pyrazinamide | ND | ND | Study data being evaluated. |
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| Methadone | ND | No significant effect | No apparent effect of rifabutin on either peak levels of methadone or systemic exposure based upon AUC. Rifabutin kinetics not evaluated. |
| Ethinylestradiol | ND | 35%↓ AUC 20%↓ Cmax |
Patients should be advised to use other methods of contraception. |
| Norethindrone | ND | 46%↓ AUC | Patients should be advised to use other methods of contraception. |
| Tacrolimus | ND | ND | Authors report that rifabutin decreases tacrolimus trough blood levels. |
| Theophylline | ND | No significant change in AUC or Cmax compared with baseline. | |
| Drugs That are Affected by Ciprofloxacin | ||
|---|---|---|
| Drug(s) | Recommendation | Comments |
| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ |
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [ |
| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [ |
| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine | Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant (for example, warfarin). |
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [ |
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil | Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity [ |
| Duloxetine | Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity. |
| Caffeine/Xanthine Derivatives | Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
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| Probenecid | Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) | Potentiation of ciprofloxacin toxicity may occur. |
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Hepatitis C protease inhibitor (boceprevir) |
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) | Do not exceed 40 mg atorvastatin daily |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( |
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Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology ( |
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During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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| * Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects ** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects *** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg q24h) **** Non-Steroidal Anti-Inflammatory Drug ***** Non-Nucleoside Reverse Transcriptase Inhibitors |
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| Sirolimus* (CYP3A4 Inhibition) |
Significantly Increased |
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| Rifabutin* (CYP3A4 Inhibition) |
Significantly Increased |
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| Efavirenz (400 mg q24h)** (CYP3A4 Inhibition) |
Significantly Increased |
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Slight Increase in AUCτ | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
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| Low-dose Ritonavir (100 mg q12h)** | Slight Decrease in Ritonavir Cmax and AUCτ | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
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| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
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| Cyclosporine* (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone*** (CYP3A4 Inhibition) |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) |
Increased | Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| Alfentanil (CYP3A4 Inhibition) |
Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablets. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ |
| Oxycodone (CYP3A4 Inhibition) |
Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| NSAIDs**** including. ibuprofen and diclofenac (CYP2C9 Inhibition) |
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ |
| Tacrolimus* (CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin* (CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration |
| Warfarin* (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole* (CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with voriconazole tablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
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| Other NNRTIs***** (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
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Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
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Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
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Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
| Everolimus (CYP3A4 Inhibition) |
Not Studied |
Concomitant administration of voriconazole and everolimus is not recommended. |
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Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg). |
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Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Celecoxib is not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of celecoxib and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
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During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics. |
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During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ |
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Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see |
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| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
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Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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| DRUG | DESCRIPTION OF INTERACTION |
| Sulfonylureas | Hypoglycemia potentiated. |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. |
| Oral Anticoagulants | Increased bleeding. |
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| Clinical Impact: | The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology • There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. |
| Intervention: | Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs. |
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| Clinical Impact: | Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
| Intervention: | Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. |
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| Clinical Impact: | Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions |
| Intervention: | A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. |
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| Clinical Impact: | Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [ There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. |
| Intervention: | Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions |
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| Clinical Impact: | Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology |
| Intervention: | Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. |
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| Clinical Impact: | Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology |
| Intervention: | Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. |
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| Clinical Impact: | Potential for increased exposure of phenytoin. |
| Intervention: | Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. |
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| Clinical Impact: | Increased exposure of diazepam [see Clinical Pharmacology |
| Intervention: | Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
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| Clinical Impact: | Potential for increased exposure of digoxin [see Clinical Pharmacology |
| Intervention: | Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. |
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| Clinical Impact: | Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
| Intervention: | Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology |
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| Clinical Impact: | Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. |
| Intervention: | See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin. |
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| Clinical Impact: | Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. |
| Intervention: | Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
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| Clinical Impact: | Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions |
| Intervention: | Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
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| Clinical Impact: | Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
| Intervention: | Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology |
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| Clinical Impact: | There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
| Intervention: | An alternative confirmatory method should be considered to verify positive results. |
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| Clinical Impact: | There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
| Intervention: | Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole. |
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| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
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| Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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Monitor patients with concomitant use of diclofenac with anticoagulants (e.g., warfarin), antiplatelet agents
(e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding ( |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone
|
|
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Concomitant use of diclofenac and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (
Diclofenac is not a substitute for low dose aspirin for cardiovascular protection. |
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| Diuretics | |
|
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
|
|
During concomitant use of diclofenac with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (
|
| Digoxin | |
|
|
The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
|
|
During concomitant use of diclofenac and digoxin, monitor serum digoxin levels. |
| Lithium | |
|
|
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
|
|
During concomitant use of diclofenac and lithium, monitor patients for signs of lithium toxicity. |
| Methotrexate | |
|
|
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
|
|
During concomitant use of diclofenac and methotrexate, monitor patients for methotrexate toxicity. |
| Cyclosporine | |
|
|
Concomitant use of diclofenac and cyclosporine may increase cyclosporine's nephrotoxicity. |
|
|
During concomitant use of diclofenac and cyclosporine, monitor patients for signs of worsening renal function. |
| NSAIDs and Salicylates | |
|
|
Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (
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The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. |
| Pemetrexed | |
|
|
Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexedassociated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
|
|
During concomitant use of diclofenac and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
| CYP2C9 Inhibitors or Inducers: | |
|
|
Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac. |
|
|
A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP450 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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| Clinical Impact: |
( Piroxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of piroxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. ( Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
| Intervention: |
Monitor patients with concomitant use of Piroxicam Capsules USP with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see |
|
|
|
| Clinical Impact: |
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see |
| Intervention: |
Concomitant use of Piroxicam Capsules USP and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see |
|
|
|
| Clinical Impact: |
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
| Intervention: |
During concomitant use of Piroxicam Capsules USP and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Piroxicam Capsules USP and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see |
|
|
|
| Clinical Impact: |
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
| Intervention: |
During concomitant use of Piroxicam Capsules USP with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see |
|
|
|
| Clinical Impact: |
The concomitant use of piroxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
| Intervention: |
During concomitant use of Piroxicam Capsules USP and digoxin, monitor serum digoxin levels. |
|
|
|
| Clinical Impact: |
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
| Intervention: |
During concomitant use of Piroxicam Capsules USP and lithium, monitor patients for signs of lithium toxicity. |
|
|
|
| Clinical Impact: |
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
| Intervention: |
During concomitant use of Piroxicam Capsules USP and methotrexate, monitor patients for methotrexate toxicity. |
|
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| Clinical Impact: |
Concomitant use of Piroxicam Capsules USP and cyclosporine may increase cyclosporine’s nephrotoxicity. |
| Intervention: |
During concomitant use of Piroxicam Capsules USP and cyclosporine, monitor patients for signs of worsening renal function. |
|
|
|
| Clinical Impact: |
Concomitant use of piroxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see |
| Intervention: |
The concomitant use of piroxicam with other NSAIDs or salicylates is not recommended. |
|
|
|
| Clinical Impact: |
Concomitant use of Piroxicam Capsules USP and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
| Intervention: |
During concomitant use of Piroxicam Capsules USP and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
|
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| Clinical Impact: |
Piroxicam Capsules USP is highly protein bound and, therefore, might be expected to displace other protein bound drugs. |
| Intervention: |
Physicians should closely monitor patients for a change in dosage requirements when administering Piroxicam Capsules USP to patients on other highly protein bound drugs. |
|
|
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| Clinical Impact: |
Concomitant use of corticosteroids with Piroxicam Capsules USP may increase the risk of GI ulceration or bleeding. |
| Intervention: |
Monitor patients with concomitant use of Piroxicam Capsules USP with corticosteroids for signs of bleeding [see |
| *Change relative to reference
|
|||||
| Coadministered Drug
|
Dosing Schedule
|
Effect on Active Moiety
(Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose
Recommendation |
||
| Coadministered Drug
|
Risperidone
|
AUC
|
Cmax
|
||
| Enzyme (CYP2D6) inhibitors
|
|
|
|
|
|
| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice daily
|
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
-
|
Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day
|
4 mg/day
|
1.6
|
-
|
||
| 40 mg/day
|
4 mg/day
|
1.8
|
-
|
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| Enzyme (CYP3A/ PgP inducers) Inducers
|
|
|
|
|
|
| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) inhibitors
|
|
|
|
|
|
| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not needed
|
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not needed
|
| Erythromycin
|
500 mg four times daily
|
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not needed
|
| Other Drugs
|
|
|
|
|
|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not Needed
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| NA – Not available/reported | |||
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|
Concentration Increase |
Increase |
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diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole, |
|
||
|
|
|||
|
cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine |
|
||
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|
were studied but reported no significant changes on digoxin exposure. |
|
||
|
|
|
|
|
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
|
|
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|
|
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
|
|
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. |
|
|
|
|
|
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted
|
|
|
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. |
|
|
|
|
|
|
|
|
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition
There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. |
|
|
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy
|
|
|
|
|
|
Increased exposure of citalopram leading to an increased risk of QT prolongation
|
|
|
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. |
|
|
|
|
|
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol)
|
|
|
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. |
|
|
|
|
|
Potential for increased exposure of phenytoin. |
|
|
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. |
|
|
|
|
|
Increased exposure of diazepam
|
|
|
Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
|
|
|
|
|
Potential for increased exposure of digoxin
|
|
|
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. |
|
|
|
|
|
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
|
|
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF
See the prescribing information for other drugs dependent on gastric pH for absorption. |
|
|
|
|
|
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. |
| Amoxicillin also has drug interactions. | |
|
|
See
See |
|
|
|
|
|
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. |
|
|
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
|
|
|
|
|
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors
|
|
|
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
|
|
|
|
|
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
|
|
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline
|
|
|
|
|
|
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
|
|
An alternative confirmatory method should be considered to verify positive results. |
|
|
|
|
|
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
|
|
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole. |
|
|
|
|
|
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome. |
|
|
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue |
|
|
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
|
|
|
|
|
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias. |
|
|
Concomitant use of pimozide and sertraline hydrochloride is contraindicated |
|
|
|
|
|
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome. |
|
|
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs |
|
|
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort |
|
|
|
|
|
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding. |
|
|
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio |
|
|
aspirin, clopidogrel, heparin, warfarin |
|
|
|
|
|
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma |
|
|
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted. |
|
|
warfarin |
|
|
|
|
|
Sertraline hydrochloride is a CYP2D6 inhibitor |
|
|
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued. |
|
|
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine |
|
|
|
|
|
Phenytoin is a narrow therapeutic index drug. sertraline hydrochloride may increase phenytoin concentrations. |
|
|
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed. |
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phenytoin, fosphenytoin |
| NA = Not available/reported | |||
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Concentration Increase |
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| diltiazem | fluconazole | azithromycin | methylprednisolone | Allopurinol |
| nicardipine | itraconazole | clarithromycin | Amiodarone | |
| verapamil | ketoconazole | erythromycin | Bromocriptine | |
| voriconazole | quinupristin/ dalfopristin | colchicine | ||
| danazol | ||||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
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1 = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
2 = Is not administered but is an active metabolite of carbamazepine. NC=Less than 10% change in plasma concentration NE=Not Evaluated |
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StrongCYP3A4Inhibitors (e.g.,itraconazole,clarithromycin) or strongCYP2D6inhibitors (e.g.,quinidine,fluoxetine,paroxetine) |
The concomitant use of aripiprazole tablets withstrong CYP3A4 orCYP2D6inhibitorsincreasedthe exposure ofaripiprazole tabletscomparedto the use of aripiprazole tabletsalone |
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inhibitororCYP2D6inhibitor, reducethearipiprazole tablets dosage |
| StrongCYP3A4Inducers (e.g.,carbamazepine,rifampin) |
The concomitant use of aripiprazole tabletsandcarbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone |
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inducer, consider increasing the aripiprazole tabletsdosage |
| AntihypertensiveDrugs |
Duetoitsalphaadrenergicantagonism,aripiprazole tablets hasthepotentialtoenhance the effect of certainantihypertensive agents. |
Monitor bloodpressureand adjustdoseaccordingly |
| Benzodiazepines(e.g., lorazepam) |
Theintensityofsedationwas greaterwith the combination of oral aripiprazole tabletsandlorazepam as comparedtothat observedwith aripiprazole alone.Theorthostatichypotension observed wasgreaterwith the combination as comparedtothatobserved withlorazepamalone |
Monitorsedation and blood pressure.Adjust dose accordingly. |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9- Hydroxy-Risperidone (Ratio*) | Risperidone Dose Recommendation | ||
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| Concomitant Drug Class:
Drug Name |
Effect on Concentration of Raltegravir | Clinical Comment |
|---|---|---|
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| aluminum and/or magnesium-containing antacids | ↓ | Coadministration or staggered administration of aluminum and/or magnesium hydroxide-containing antacids and ISENTRESS is not recommended. |
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| rifampin | ↓ | The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age
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Multivalent cation-containing products including antacids, metal cation or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. |
|
Warfarin |
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Antidiabetic agent |
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Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg). |
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Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Celecoxib is not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
|
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During concomitant use of celecoxib and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
|
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During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics. |
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During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
|
|
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ |
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Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding. |
|
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Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| |
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| |
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| |
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine |
Decreased lamotrigine levels approximately 50%. |
| |
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| |
? CBZ epoxide |
May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40% |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40% |
| Valproate |
↑ lamotrigine |
Increased lamotrigine concentrations slightly more than 2-fold. |
| |
? valproate |
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| * The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable | |
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| Azoles |
Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole |
| Antineoplastic agents |
Irinotecan, paclitaxel, teniposide |
| Delavirdine |
Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance |
| Neuromuscular blocking agents |
Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. |
| Warfarin |
Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin |
| Other |
Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D |
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|
| Antiepileptic drugs* |
Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, |
| Antilipidemic agents |
Atorvastatin, fluvastatin, simvastatin |
| Antiviral agents |
Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir |
| Calcium channel blockers |
Nifedipine, nimodipine, nisoldipine, verapamil |
| Other |
Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine |
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|
| nafcillin | carbamazepine | bosentan |
| rifampin | oxcarbazepine | octreotide |
| phenobarbital | orlistat | |
| phenytoin | sulfinpyrazone | |
| terbinafine | ||
| ticlopidine | ||
|
|
| Drugs that Affect Renal Function |
A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin. |
|
| Antiarrthymics | Dofetilide | Concomitant administration with digoxin was associated with a higher rate of torsades de pointes. |
| Sotalol | Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. | |
| Dronedarone | Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin. | |
| Parathyroid Hormone Analog |
Teriparatide | Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. |
| Thyroid supplement | Thyroid | Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. |
| Sympathomimetics | Epinephrine Norepinephrine Dopamine | Can increase the risk of cardiac arrhythmias. |
| Neuromuscular Blocking Agents |
Succinylcholine | May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin. |
| Supplements | Calcium | If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. |
| Beta-adrenergic blockers and calcium channel blockers |
Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block. | |
| Ivabradine | Can increase the risk of bradycardia. | |
|
|
|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| 1nc denotes a mean change of less than 10% | ||||
| 2Pediatrics | ||||
| 3Mean increase in adults at high oxcarbazepine doses | ||||
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[CI: 17% decrease, 57% decrease] |
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[CI: 2% increase, 24% increase] |
[CI: 12% decrease, 51% decrease] |
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>1200 to 2400 |
up to 40% increase 3 [CI: 12% increase, 60% increase] |
[CI: 3% decrease, 48% decrease] |
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[CI: 13% decrease, 40% decrease] |
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The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
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Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue
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selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
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Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
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Concomitant use of pimozide and sertraline hydrochloride is contraindicated
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The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
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Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs
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other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
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The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
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Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio
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aspirin, clopidogrel, heparin, warfarin
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Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma
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Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
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warfarin
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Sertraline hydrochloride is a CYP2D6 inhibitor
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Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
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propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
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Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
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Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
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phenytoin, fosphenytoin
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| * The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable | |
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Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole. |
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Dose adjustment of paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor. |
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Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol. |
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Recommend to take paricalcitol capsules at least 1 hour |
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Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol. |
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Recommend to take paricalcitol capsules at least 1 hour |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide
|
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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|
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|
|
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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|
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|
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||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
|
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
|
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 | ||
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|
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|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 | ||
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|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 | ||
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|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
|
| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
| *Refer to for information regarding table.
|
|||
| albuterol, systemic and inhaled | felodipinefinasteride | nizatidinenorfloxacin | |
| amoxicillin | hydrocortisone | ofloxacin | |
| ampicillin, with or without sulbactam | isoflurane isoniazid | omeprazole prednisone, prednisolone | |
| atenolol | isradipine | ranitidine | |
| azithromycin | influenza vaccine | rifabutin | |
| caffeine, dietary ingestion | ketoconazo lelomefloxacin | roxithromycin sorbitol | |
| cefaclor | mebendazole | (purgative doses do not | |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | medroxyprogesteronemethylprednisolone | inhibit theophylline absorption) | |
| diltiazem | metronidazole | sucralfate | |
| dirithromycin | metoprolol | terbutaline, systemic | |
| enflurane | nadolol | terfenadine | |
| famotidine | nifedipine | tetracycline | |
| tocainide | |||
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|
Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
|
Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( |
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Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
|
|
During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( |
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|
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
|
|
During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( |
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The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
|
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During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
|
|
During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics. |
|
|
During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( |
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|
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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|
During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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|
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
|
|
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology ( |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology ( |
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Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. |
|
|
Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions ( |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose |
| Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. | |
|
|
|
| Calcium Carbonate
Ferrous Sulfate |
Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents. |
| Orlistat | Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function. |
| Bile Acid Sequestrants
- Colesevelam - Cholestyramine - Colestipol Ion Exchange Resins - Kayexalate - Sevelamer |
Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels. |
| Other drugs:
Proton Pump Inhibitors Sucralfate Antacids - Aluminum & Magnesium Hydroxides - Simethicone |
Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately. |
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and cooked sliced ham) |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
| AED Co-administered | AED Concentration | Topiramate Concentration |
|---|---|---|
| NC = Less than 10% change in plasma concentration. NE = Not Evaluated |
||
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
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|
| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate |
| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs |
| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine | Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin |
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil | Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine | Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity. |
| Caffeine/Xanthine Derivatives | Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
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|
||
| Probenecid | Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
| Drugs that Affect Renal Function |
A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin. |
|
| Antiarrthymics | Dofetilide | Concomitant administration with digoxin was associated with a higher rate of torsades de pointes. |
| Sotalol | Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. | |
| Dronedarone | Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin. | |
| Parathyroid Hormone Analog |
Teriparatide | Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. |
| Thyroid supplement | Thyroid | Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. |
| Sympathomimetics | Epinephrine Norepinephrine Dopamine | Can increase the risk of cardiac arrhythmias. |
| Neuromuscular Blocking Agents |
Succinylcholine | May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin. |
| Supplements | Calcium | If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. |
| Beta-adrenergic blockers and calcium channel blockers |
Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block. | |
| Ivabradine | Can increase the risk of bradycardia. | |
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| Concomitant Drug
|
Effect on Concentration of
Lamotrigine or Concomitant Drug |
Clinical Comment
|
| Estrogen-containing oral
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine
↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide
|
↓ lamotrigine
? carbamazepine epoxide |
Addition of carbamazepine decreases
lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 50%.
|
| Atazanavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine AUC approximately 32%.
|
| Phenobarbital/Primidone
|
↓ lamotrigine
|
Decreased lamotrigine concentration
approximately 40%. |
| Phenytoin
|
↓ lamotrigine
|
Decreased lamotrigine concentration
approximately 40%. |
| Rifampin
|
↓ lamotrigine
|
Decreased lamotrigine AUC
approximately 40%. |
| Valproate
|
↑ lamotrigine
? valproate |
Increased lamotrigine concentrations
slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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|||||
| Coadministered Drug
|
Dosing Schedule
|
Effect on Active
Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose
Recommendation |
||
|
|
Coadministered Drug
|
Risperidone
|
AUC
|
Cmax
|
|
| Enzyme (CYP2D6)
Inhibitors |
|
|
|
|
|
| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice
daily |
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day
|
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
|
Re-evaluate dosing.
|
|
|
20 mg/day
|
4 mg/day
|
1.6
|
|
Do not exceed 8 mg/day
|
|
|
40 mg/day
|
4 mg/day
|
1.8
|
|
|
| Enzyme (CYP3A/ PgP inducers) Inducers
|
|
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|
|
|
| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards.
Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)
Inhibitors |
|
|
|
|
|
| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not
needed |
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not
needed |
| Erythromycin
|
500 mg four times
daily |
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not
needed |
|
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|
| Other Drugs
|
|
|
|
|
|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not
needed |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (
|
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
|
| Antidiabetic agents | Carefully monitor blood glucose (
|
|
|
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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|
|
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
|
|
During concomitant use of Indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin capsules and triamterene should not be administered together. Both Indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. |
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Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [ |
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Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. |
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NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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Monitor patients with concomitant use of PONSTEL with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone |
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Concomitant use of PONSTEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see PONSTEL is not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of PONSTEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects |
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The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of PONSTEL and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
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During concomitant use of PONSTEL and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of PONSTEL and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of PONSTEL and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of PONSTEL and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy |
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The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended. |
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Concomitant use of PONSTEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of PONSTEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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In a single dose study (n=6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively. |
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Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events . |
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| Coadministered Drug | Dosing Schedule |
Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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|---|---|---|
| ↓ = Decreased (induces lamotrigine glucuronidation) ↑ = Increased (inhibits lamotrigine glucuronidation) ? = Conflicting data |
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epoxide |
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epoxide |
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| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
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Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Multivalent cation-containing products including : antacids, sucralfate, multivitamins |
Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride at least 4 hours before or 8 hours after these products. ( |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. ( |
| Class IA and Class III antiarrhythmics: |
Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
| Antidiabetic agents |
Carefully monitor blood glucose. ( |
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Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (
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Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. |
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Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis |
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Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. |
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Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). |
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Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
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|
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
|
| ↓levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
|
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone |
|
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
|
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
|
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
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| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| |
|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| *Change relative to reference |
|||||
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose Recommendation |
||
| Coadministered Drug |
Risperidone |
AUC |
Cmax |
||
| Enzyme (CYP2D6) inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day |
4 mg/day |
1.6 |
- |
||
| 40 mg/day |
4 mg/day |
1.8 |
- |
||
| Enzyme (CYP3A/ PgP inducers) Inducers |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
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|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not Needed |
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Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (
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|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
|
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis |
|
|
|
|
|
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. |
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Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
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|
|
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). |
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Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
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Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
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Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
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Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
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Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
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These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Etravirine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↑ = increase, ↓ = decrease, ↔ = no change | ||
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| efavirenz nevirapine |
↓ etravirine | Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered. |
| delavirdine | ↑ etravirine | Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered. |
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| atazanavir (without ritonavir) |
↓ atazanavir | Concomitant use of INTELENCE® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir. |
| atazanavir/ritonavir |
↓ atazanavir ↑ etravirine |
Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered. |
| darunavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments. |
| fosamprenavir (without ritonavir) |
↑ amprenavir | Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir. |
| fosamprenavir/ritonavir |
↑ amprenavir | Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered. |
| indinavir (without ritonavir) |
↓ indinavir | Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir. |
| lopinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments. |
| nelfinavir (without ritonavir) |
↑ nelfinavir | Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir. |
| ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with ritonavir 600 mg b.i.d. may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg b.i.d. should not be co-administered. |
| saquinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments. |
| tipranavir/ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered. |
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| maraviroc |
↔ etravirine ↓ maraviroc |
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg b.i.d. No dose adjustment of INTELENCE® is needed. |
| maraviroc/darunavir/ritonavir |
↔ etravirine ↑ maraviroc |
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg b.i.d. No dose adjustment of INTELENCE® is needed. |
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digoxin |
↔ etravirine ↑ digoxin |
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. |
| amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine |
↓ antiarrhythmics | Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available. |
|
warfarin |
↑ anticoagulants | Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®. |
|
carbamazepine, phenobarbital, phenytoin |
↓ etravirine | Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
|
fluconazole voriconazole |
↑ etravirine ↔ fluconazole ↑ voriconazole |
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed. |
| Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed. | ||
|
itraconazole, ketoconazole, posaconazole |
↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole |
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs. |
|
clarithromycin |
↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin |
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against |
|
rifampin, rifapentine |
↓ etravirine | Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
|
rifabutin |
↓ etravirine ↓ rifabutin ↓ 25- |
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg q.d. is recommended. If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure. |
|
diazepam |
↑ diazepam | Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. |
|
dexamethasone (systemic) |
↓ etravirine | Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use. |
|
St. John's wort ( |
↓ etravirine | Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered. |
|
atorvastatin fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin |
↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin |
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin is metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary. |
|
cyclosporine, sirolimus, tacrolimus |
↓ immunosuppressant | INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected. |
|
methadone |
↔ etravirine ↔ methadone |
INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
|
sildenafil vardenafil, tadalafil |
↓ sildenafil ↓ N-desmethyl-sildenafil |
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect. |
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clopidogrel |
↓ clopidogrel (active) metabolite | Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered. |
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The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
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Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue
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selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
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Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
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Concomitant use of pimozide and sertraline hydrochloride is contraindicated
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The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
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Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs
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other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
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The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
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Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio
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aspirin, clopidogrel, heparin, warfarin
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Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma
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Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
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warfarin
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Sertraline hydrochloride is a CYP2D6 inhibitor
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Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
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propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
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Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
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Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
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phenytoin, fosphenytoin
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Administer half of usual dose |
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Administer a quarter of usual dose |
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Strong CYP2D6 |
Administer half of usual dose |
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Strong CYP2D6 |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Raltegravir | Clinical Comment |
|---|---|---|
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| atazanavir | ↑ | Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| atazanavir/ritonavir | ↑ | Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| efavirenz | ↓ | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| etravirine | ↓ | Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| tipranavir/ritonavir | ↓ | Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended. |
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| omeprazole | ↑ | Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| rifampin | ↓ | Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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Nevirapine or Concomitant Drug |
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| Atazanavir/Ritonavir* |
↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with
atazanavir because nevirapine substantially decreases atazanavir exposure
and there is a potential risk for nevirapine-associated toxicity due
to increased nevirapine exposures. |
| Fosamprenavir* |
↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir
without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir* |
↓ Amprenavir ↑ Nevirapine |
No dosing adjustments are required when nevirapine is co-administered
with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination
of nevirapine administered with fosamprenavir/ritonavir once daily
has not been studied. |
| Indinavir* |
↓ Indinavir |
The appropriate doses of this combination of indinavir
and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* |
↓Lopinavir |
Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* |
↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine
and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir |
The interaction between nevirapine and
saquinavir/ritonavir has not been evaluated |
The appropriate doses of the
combination of nevirapine and saquinavir/ritonavir with respect to
safety and efficacy have not been established. |
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| Efavirenz* |
↓ Efavirenz |
The appropriate doses of these combinations with
respect to safety and efficacy have not been established. |
| Delavirdine Etravirine Rilpivirine |
Plasma concentrations may be altered. Nevirapine
should not be coadministered with another NNRTI as this combination
has not been shown to be beneficial. |
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| Boceprevir |
Plasma concentrations of boceprevir may
be decreased due to induction of CYP3A4/5 by nevirapine. |
Nevirapine and boceprevir
should not be coadministered because decreases in boceprevir plasma
concentrations may result in a reduction in efficacy. |
| Telaprevir |
Plasma concentrations of telaprevir may
be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations
of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. |
Nevirapine and telaprevir
should not be coadministered because changes in plasma concentrations
of nevirapine, telaprevir, or both may result in a reduction in telaprevir
efficacy or an increase in nevirapine-associated adverse events. |
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| Methadone* |
↓ Methadone |
Methadone levels were decreased;
increased dosages may be required to prevent symptoms of opiate withdrawal.
Methadone-maintained patients beginning nevirapine therapy should
be monitored for evidence of withdrawal and methadone dose should
be adjusted accordingly. |
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| Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have
not been established. |
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| Clarithromycin* |
↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine;
however, 14-OH metabolite concentrations were increased. Because
clarithromycin active metabolite has reduced activity against |
| Rifabutin* |
↑ Rifabutin |
Rifabutin and its metabolite concentrations were moderately increased.
Due to high intersubject variability, however, some patients may
experience large increases in rifabutin exposure and may be at higher
risk for rifabutin toxicity. Therefore, caution should be used in
concomitant administration. |
| Rifampin* |
↓ Nevirapine |
Nevirapine and rifampin should not be administered
concomitantly because decreases in nevirapine plasma concentrations
may reduce the efficacy of the drug. Physicians needing to treat
patients co-infected with tuberculosis and using a nevirapine-containing
regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
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| Fluconazole* |
↑Nevirapine |
Because of the risk of increased exposure to nevirapine, caution
should be used in concomitant administration, and patients should
be monitored closely for nevirapine-associated adverse events. |
| Ketoconazole* |
↓ Ketoconazole |
Nevirapine and ketoconazole should not be administered concomitantly
because decreases in ketoconazole plasma concentrations may reduce
the efficacy of the drug. |
| Itraconazole |
↓ Itraconazole |
Nevirapine and itraconazole should not be administered
concomitantly due to potential decreases in itraconazole plasma concentrations
that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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| Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Despite lower ethinyl estradiol and norethindrone
exposures when coadministered with nevirapine, literature reports
suggest that nevirapine has no effect on pregnancy rates among HIV-infected
women on combined oral contraceptives. When coadministered with VIRAMUNE
XR, no dose adjustment of ethinyl estradiol or norethindrone is needed
when used in combination for contraception When oral contraceptives are used for hormonal regulation during VIRAMUNE XR therapy, the therapeutic effect of the hormonal therapy should be monitored. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| AED Co-administered
|
AED Concentration
|
Topiramate Concentration
|
| Phenytoin
|
NC or 25% increase
a
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
b
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
| Concomitant Drug Class: Drug Name | Effect on Concentration |
Clinical Comment |
|---|---|---|
|
antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate) |
↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake) |
The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA. |
|
rifabutin |
↓ rilpivirine |
Concomitant use of COMPLERA with rifabutin may cause significant decreases in rilpivirine plasma concentrations (induction of CYP3A enzymes). If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of rifabutin coadministration. |
|
fluconazole itraconazole ketoconazole posaconazole voriconazole |
↑ rilpivirine ↓ ketoconazole |
Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA. |
|
ledipasvir/sofosbuvir |
↑ tenofovir |
Patients receiving COMPLERA concomitantly with HARVONI™ (ledipasvir/sofosbuvir) should be monitored for adverse reactions associated with tenofovir disoproxil fumarate. |
|
cimetidine famotidine nizatidine ranitidine |
↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) ↓ rilpivirine (famotidine taken 2 hours before rilpivirine) |
The combination of COMPLERA and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA. |
|
clarithromycin erythromycin telithromycin |
↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin |
Concomitant use of COMPLERA with clarithromycin, erythromycin, or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered. |
|
methadone |
↓ R(–) methadone ↓ S(+) methadone ↔ rilpivirine ↔ methadone |
No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
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|
| Antacids, sucralfate, multivitamins, and other products containing multivalent cations | Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin | Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
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|
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide | ↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| Drug | Effect | |
|---|---|---|
| Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). |
Cardiac pressor response potentiated. May cause acute hypertensive crisis. |
|
| Phenylephrine with tricyclic anti-depressants. |
Pressor response increased. |
|
| Phenylephrine with ergot alkaloids. |
Excessive rise in blood pressure. |
|
| Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. |
Tachycardia or other arrhythmias may occur. | |
| Phenylephrine with prior administration of propranolol or other β-adrenergic blockers. |
Cardiostimulating effects blocked. | |
| Phenylephrine with atropine sulfate. |
Reflex bradycardia blocked; pressor response enhanced. |
|
| Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. |
Pressor response decreased. | |
| Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. |
Synergistic adrenergic response. |
| |
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
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|
|
|---|---|---|
| * The interaction between SUSTIVA and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. | ||
| This table is not all-inclusive. | ||
|
|
||
| Protease inhibitor: Fosamprenavir calcium |
↓ amprenavir |
Fosamprenavir
(unboosted): Appropriate doses of the combinations with respect to safety
and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when SUSTIVA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: Atazanavir sulfate |
↓ atazanavir* |
|
| Protease inhibitor: Indinavir |
↓ indinavir* |
The optimal dose of indinavir, when given in combination with SUSTIVA, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC and Cmin were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone. |
| Protease inhibitor: Lopinavir/ritonavir |
↓ lopinavir* |
Lopinavir/ritonavir tablets should not be administered once daily in combination with SUSTIVA. In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with SUSTIVA with no dose adjustment. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with SUSTIVA in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with SUSTIVA. |
| Protease inhibitor: Ritonavir |
↑ ritonavir* ↑ efavirenz* |
When ritonavir 500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when SUSTIVA is used in combination with ritonavir. |
| Protease inhibitor: Saquinavir |
↓ saquinavir* |
Should not be used as sole protease inhibitor in combination with SUSTIVA. |
| NNRTI: Other NNRTIs |
↑ or ↓ efavirenz and/or NNRTI |
Combining two NNRTIs has not been shown to be beneficial. SUSTIVA should not be coadministered with other NNRTIs. |
| CCR5 co-receptor antagonist: Maraviroc |
↓ maraviroc* |
Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz. |
| Integrase strand transfer inhibitor: Raltegravir |
↓ raltegravir* |
SUSTIVA reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
|
|
||
| Protease inhibitor: Boceprevir |
↓ boceprevir* |
Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided. |
| Protease inhibitor: Telaprevir |
↓ telaprevir* ↓ efavirenz* |
Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz. |
|
|
||
| Anticoagulant: Warfarin |
↑ or ↓ warfarin |
Plasma concentrations and effects potentially increased or decreased by SUSTIVA. |
| Anticonvulsants: Carbamazepine |
↓ carbamazepine* ↓ efavirenz* |
There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used. |
| Phenytoin Phenobarbital |
↓ anticonvulsant ↓ efavirenz |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants: Bupropion |
↓ bupropion* |
The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| Sertraline | ↓ sertraline* | Increases in sertraline dosage should be guided by clinical response. |
| Antifungals: Voriconazole |
↓ voriconazole* ↑ efavirenz* |
SUSTIVA and voriconazole must not be coadministered at standard doses. Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of SUSTIVA-associated side effects. When voriconazole is coadministered with SUSTIVA, voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation. SUSTIVA tablets should not be broken. [See |
|
Itraconazole |
↓ itraconazole* ↓ hydroxyitraconazole* |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| Ketoconazole | ↓ ketoconazole | Drug interaction studies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA has the potential to decrease plasma concentrations of ketoconazole. |
| Posaconazole | ↓ posaconazole* | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective: Clarithromycin |
↓ clarithromycin* ↑ 14-OH metabolite* |
Plasma concentrations
decreased by SUSTIVA; clinical significance unknown. In uninfected volunteers,
46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment
of SUSTIVA is recommended when given with clarithromycin. Alternatives to
clarithromycin, such as azithromycin, should be considered (see |
| Antimycobacterials: Rifabutin |
↓ rifabutin* |
Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| Rifampin | ↓ efavirenz* | If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended. |
| Calcium channel blockers: Diltiazem |
↓ diltiazem* ↓ desacetyl diltiazem* ↓ N-monodesmethyl diltiazem* |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem. |
| Others (eg, felodipine, nicardipine, nifedipine, verapamil) |
↓ calcium channel blocker |
No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase
inhibitors: Atorvastatin Pravastatin Simvastatin |
↓ atorvastatin* ↓ pravastatin* ↓ simvastatin* |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: Oral Ethinyl estradiol/ Norgestimate |
↓ active metabolites of norgestimate* |
A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant Etonogestrel |
↓ etonogestrel |
A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immunosuppressant |
Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz. |
| Narcotic analgesic: Methadone |
↓ methadone* |
Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
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|
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
|
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|
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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↑ Zidovudine |
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↔ MMF (in patients with normal renal function) |
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↑ Didanosine |
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| Coadministered drug | Dosing regimen of coadministered drug | Dosing regimen of rifabutin | Study population (n) | Effect on rifabutin | Effect on coadministered drug | Recommendation |
|---|---|---|---|---|---|---|
| ↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD- once daily; BID- twice daily; TID – thrice daily ND - No Data AUC - Area under the Concentration vs. Time Curve; C max - Maximum serum concentration |
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| Amprenavir | 1200 mg BID × 10 days | 300 mg QD × 10 days | Healthy male subjects (6) | ↑ AUC by 193%,
↑ Cmax by 119% |
↔ | Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions. |
| Delavirdine | 400 mg TID | 300 mg QD | HIV-infected patients (7) | ↑ AUC by 230%,
↑ Cmax by 128% |
↓ AUC by 80%,
↓ Cmax by 75%, ↓ Cmin by 17% |
|
| Didanosine | 167 or 250 mg BID × 12 days | 300 or 600 mg QD × 1 | HIV-infected patients (11) | ↔ | ↔ | |
| Fosamprenavir/ ritonavir | 700 mg BID plus ritonavir 100 mg BID × 2 weeks | 150 mg every other day × 2 weeks | Healthy subjects (15) | ↔ AUC
↓ Cmax by 15% |
↑ AUC by 35%
↑ Cmax by 36%, ↑ Cmin by 36%, |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination. |
| Indinavir | 800 mg TID × 10 days | 300 mg QD × 10 days | Healthy subjects (10) | ↑ AUC by 173%,
↑ Cmax by 134% |
↓ AUC by 34%,
↓ Cmax by 25%, ↓ Cmin by 39% |
Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID. |
| Lopinavir/ ritonavir | 400/100 mg BID × 20 days | 150 mg QD × 10 days | Healthy subjects (14) | ↑ AUC by 203%
↓ Cmax by 112% |
↔ | Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Saquinavir/ ritonavir | 1000/100 mg BID × 14 or 22 days | 150 mg every 3 days × 21–22 days | Healthy subjects | ↑ AUC by 53%
↑ Cmax by 88% (n=11) |
↓ AUC by 13%,
↓ Cmax by 15%, (n=19) |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions. |
| Ritonavir | 500mg BID × 10 days | 150 mg QD × 16 days | Healthy subjects (5) | ↑ AUC by 300%,
↑ Cmax by 150% |
ND | Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions.
Reduce rifabutin dosage further, as needed. |
| Tipranavir/ ritonavir | 500/200 BID × 15 doses | 150 mg single dose | Healthy subjects (20) | ↑ AUC by 190%,
↑ Cmax by 70% |
↔ | Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Nelfinavir | 1250 mg BID × 7–8 days | 150 mg QD × 8 days | HIV-infected patients (11) | ↑ AUC by 83%,
↑ Cmax by 19% |
↔ | Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID |
| Zidovudine | 100 or 200 mg q4h | 300 or 450 mg QD | HIV-infected patients (16) | ↔ | ↓ AUC by 32%,
↓ Cmax by 48%, |
Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary. |
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| Fluconazole | 200 mg QD × 2 weeks | 300 mg QD × 2 weeks | HIV-infected patients (12) | ↑ AUC by 82%,
↑ Cmax by 88% |
↔ | Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend MYCOBUTIN use if toxicity is suspected. |
| Posaconazole | 200 mg QD × 10 days | 300 mg QD × 17 days | Healthy subjects (8) | ↑ AUC by 72%,
↑ Cmax by 31% |
↓ AUC by 49%,
↓ Cmax by 43% |
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy. |
| Itraconazole | 200 mg QD | 300 mg QD | HIV-Infected patients (6) | ↑
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↓ AUC by 70%,
↓ Cmax by 75%, |
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following co-administration of rifabutin (300 mg QD) with itraconazole (600–900 mg QD). |
| Voriconazole | 400 mg BID × 7 days (maintenance dose) | 300 mg QD × 7 days | Healthy male subjects (12) | ↑ AUC by 331%,
↑ Cmax by 195% |
↑ AUC by ~100%,
↑ Cmax by ~100% |
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| Dapsone | 50 mg QD | 300 mg QD | HIV-infected patients (16) | ND | ↓ AUC by 27 –40% | |
| Sulfamethoxazole- Trimethoprim | 800/160 mg | 300 mg QD | HIV-infected patients (12) | ↔ | ↓ AUC by 15–20% | |
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| Azithromycin | 500 mg QD × 1 day, then 250 mg QD × 9 days | 300 mg QD | Healthy subjects (6) | ↔ | ↔ | |
| Clarithromycin | 500 mg BID | 300 mg QD | HIV-infected patients (12) | ↑ AUC by 75% | ↓ AUC by 50% | Monitor for rifabutin associated adverse events. Reduce dose or suspend use of MYCOBUTIN if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin |
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| Ethambutol | 1200 mg | 300 mg QD × 7 days | Healthy subjects (10) | ND | ↔ | |
| Isoniazid | 300 mg | 300 mg QD × 7 days | Healthy subjects (6) | ND | ↔ | |
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| Methadone | 20 – 100 mg QD | 300 mg QD × 13 days | HIV-infected patients (24) | ND | ↔ | |
| Ethinylestradiol (EE)/Norethindrone (NE) | 35 mg EE / 1 mg NE × 21 days | 300 mg QD × 10 days | Healthy female subjects (22) | ND | EE: ↓ AUC by
35%, ↓ C max by 20% NE: ↓ AUC by 46% |
Patients should be advised to use additional or alternative methods of contraception. |
| Theophylline | 5 mg/kg | 300 mg × 14 days | Healthy subjects (11) | ND | ↔ | |
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| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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Adenosine |
Theophylline blocks adenosine receptors. |
Higher doses of adenosine may be required to achieve desired effect. |
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Alcohol |
A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. |
30% increase |
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Allopurinol |
Decreases theophylline clearance at allopurinol doses ≥600 mg/day. |
25% increase |
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Aminoglutethimide |
Increases theophylline clearance by induction of microsomal enzyme activity. |
25% decrease |
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Carbamazepine |
Similar to aminoglutethimide. |
30% decrease |
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Cimetidine |
Decreases theophylline clearance by inhibiting cytochrome P450 1A2. |
70% increase |
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Ciprofloxacin |
Similar to cimetidine. |
40% increase |
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Clarithromycin |
Similar to erythromycin. |
25% increase |
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Diazepam |
Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. |
Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
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Disulfiram |
Decreases theophylline clearance by inhibiting hydroxylation and demethylation. |
50% increase |
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Enoxacin |
Similar to cimetidine. |
300% increase |
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Ephedrine |
Synergistic CNS effects. |
Increased frequency of nausea, nervousness, and insomnia. |
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Erythromycin |
Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. |
35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
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Estrogen |
Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. |
30% increase |
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Flurazepam |
Similar to diazepam. |
Similar to diazepam. |
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Fluvoxamine |
Similar to cimetidine. |
Similar to cimetidine. |
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Halothane |
Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. |
Increased risk of ventricular arrhythmias. |
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Interferon, human recombinant alpha-A |
Decreases theophylline clearance. |
100% increase |
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Isoproterenol (IV) |
Increases theophylline clearance. |
20% decrease |
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Ketamine |
Pharmacologic. |
May lower theophylline seizure threshold |
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Lithium |
Theophylline increases renal lithium clearance. |
Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
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Lorazepam |
Similar to diazepam. |
Similar to diazepam. |
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Methotrexate (MTX) |
Decreases theophylline clearance. |
20% increase after low dose MTX, higher dose MTX may have a greater effect. |
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Mexiletine |
Similar to disulfiram. |
80% increase |
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Midazolam |
Similar to diazepam. |
Similar to diazepam. |
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Moricizine |
Increases theophylline clearance. |
25% decrease |
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Pancuronium |
Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. |
Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
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Pentoxifylline |
Decreases theophylline clearance. |
30% increase |
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Phenobarbital (PB) |
Similar to aminoglutethimide. |
25% decrease after two weeks of concurrent PB. |
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Phenytoin |
Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. |
Serum theophylline |
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Propafenone |
Decreases theophylline clearance and pharmacologic interaction. |
40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
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Propranolol |
Similar to cimetidine and pharmacologic interaction. |
100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
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Rifampin |
Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. |
20-40% decrease |
| St. John’sWort (Hypericum Perforatum) | Decrease in theophylline plasma concentrations. | Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity. |
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Sulfinpyrazone |
Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. |
20% decrease |
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Tacrine |
Similar to cimetidine, also increases renal clearance of theophylline. |
90% increase |
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Thiabendazole |
Decreases theophylline clearance. |
190% increase |
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Ticlopidine |
Decreases theophylline clearance. |
60% increase |
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Troleandomycin |
Similar to erythromycin. |
33-100% increase depending on troleandomycin dose. |
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Verapamil |
Similar to disulfiram. |
20% increase |
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· Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. · Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg). |
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Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection. |
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· NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). · In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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· During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. · During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ · When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
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During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). celecoxib capsules has no effect on methotrexate pharmacokinetics. |
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During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ |
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Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [ |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing
of these drugs for use in patients for whom alternative treatment
options are inadequate. Limit dosages and durations to the minimum
required. Follow patients closely for signs of respiratory depression
and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DILAUDID INJECTION and DILAUDID-HP INJECTION if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids
may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory
depression, coma) If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. |
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The use of DILAUDID INJECTION or DILAUDID-HP INJECTION is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of DILAUDID INJECTION and DILAUDID-HP INJECTION and/or precipitate withdrawal syndrome. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine, |
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Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DILAUDID INJECTION and DILAUDID-HP INJECTION and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when DILAUDID INJECTION and DILAUDID-HP INJECTION are used concomitantly with anticholinergic drugs. |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Interacting Drug | Interaction |
|---|---|
| Drugs known to prolong QT interval (e.g., Class IA and Class III anti-arrhythmic agents). | Quinine Sulfate Capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use ( |
| Other antimalarials (e.g., halofantrine, mefloquine). | ECG abnormalities including QT prolongation. Avoid concomitant use ( |
| CYP3A4 inducers or inhibitors | Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( |
| CYP3A4 and CYP2D6 substrates | Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( |
| Digoxin | Increased digoxin plasma concentration ( |
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| Antineoplastic agents usually in combination | Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate |
| Antiviral agents | Fosamprenavir, nelfinavir, ritonavir |
| Antiepileptic drugs | Carbamazepine, vigabatrin |
| Other |
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| Antiepileptic drugs | Phenobarbital, valproate sodium, valproic acid |
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Glucocorticoids Octreotide |
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Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
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Iodide(including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
|---|---|---|
| a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. AED = Antiepileptic drug. NE = Not Evaluated. TPM – Topiramate |
||
| Phenytoin | NC or 25% increasea | 48% decrease |
| Carbamazepine (CBZ) | NC 40% | decrease |
| CBZ epoxideb | NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 15% increase |
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|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide
|
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 | ||
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|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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|
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
|
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
|
||
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|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin |
NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxide |
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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↓ levonorgestrel |
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? carbamazepine epoxide |
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? valproate |
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| Drug | Description |
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia |
| Uricosuric Agents | Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited |
| Drug | Effect |
| Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). | Cardiac pressor response potentiated. May cause acute hypertensive crisis. |
| Phenylephrine with tricyclic antidepressants. | Pressor response increased. |
| Phenylephrine with ergot alkaloids. | Excessive rise in blood pressure. |
| Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. | Tachycardia or other arrhythmias may occur. |
| Phenylephrine with prior administration of propranolol or other β-adrenergic blockers. | Cardiostimulating effects blocked. |
| Phenylephrine with atropine sulfate. | Reflex bradycardia blocked; pressor response enhanced. |
| Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. | Pressor response decreased. |
| Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. | Synergistic adrenergic response. |
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Monitor patients with concomitant use of NAPRELAN with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Concomitant use of NAPRELAN and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ NAPRELAN is not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of NAPRELAN with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of NAPRELAN and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of NAPRELAN and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
|
|
During concomitant use of NAPRELAN and methotrexate, monitor patients for methotrexate toxicity. |
|
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|
|
Concomitant use of NAPRELAN and cyclosporine may increase cyclosporine’s nephrotoxicity. |
|
|
During concomitant use of NAPRELAN and cyclosporine, monitor patients for signs of worsening renal function. |
|
|
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|
|
Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
|
|
The concomitant use of naproxen sodium with other NSAIDs or salicylates is not recommended. |
|
|
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|
|
Concomitant use of NAPRELAN and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
|
|
During concomitant use of NAPRELAN and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity |
|
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|
|
Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. |
|
|
Concomitant administration of antacids such as magnesium oxide or aluminum hydroxid, and sucralfate with NAPRELAN is not recommended. |
|
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|
|
Concomitant administration of cholestyramine can delay the absorption of naproxen. |
|
|
Concomitant administration of cholestyramine with NAPRELAN is not recommended. |
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|
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Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. |
|
|
Patients simultaneously receiving NAPRELAN and probenecid should be observed for adjustment of dose if required. |
|
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|
Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. |
|
|
Patients simultaneously receiving NAPRELAN and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. |
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|
| Concomitant Drug
|
Effect onConcentration ofLamotrigine orConcomitant Drug
|
Clinical Comment
|
| Estrogen-containing oralcontraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine
↓ levonorgestrel |
Decreased lamotrigine concentrationsapproximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepineand carbamazepine epoxide
|
↓ lamotrigine
? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentrationapproximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUCapproximately 32%. |
| Phenobarbital/primidone
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 40%. |
| Rifampin
|
↓ lamotrigine
|
Decreased lamotrigine AUC approximately 40%. |
| Valproate
|
↑ lamotrigine
? valproate |
Increased lamotrigine concentrations slightly more than 2-fold.There are conflicting study resultsregarding effect of lamotrigine onvalproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change invalproate concentrations in controlled clinical trials in patients with epilepsy. |
|
|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
|
|
|
| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
|
| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
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| Concomitant Drug |
Effect onConcentration ofLamotrigine orConcomitant Drug |
Clinical Comment |
| Estrogen-containing oralcontraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine concentrationsapproximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepineand carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentrationapproximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUCapproximately 32%. |
| Phenobarbital/primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold.There are conflicting study resultsregarding effect of lamotrigine onvalproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change invalproate concentrations in controlled clinical trials in patients with epilepsy. |
|
|
|
|
|
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
|
|
|
|
|
|
|
|
|
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
|
|
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. |
|
|
|
|
|
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted |
|
|
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. |
|
|
|
|
|
|
|
|
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. |
|
|
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy |
|
|
|
|
|
Increased exposure of citalopram leading to an increased risk of QT prolongation |
|
|
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. |
|
|
|
|
|
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) |
|
|
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. |
|
|
|
|
|
Potential for increased exposure of phenytoin. |
|
|
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. |
|
|
|
|
|
Increased exposure of diazepam |
|
|
Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
|
|
|
|
|
Potential for increased exposure of digoxin |
|
|
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. |
|
|
|
|
|
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
|
|
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF See the prescribing information for other drugs dependent on gastric pH for absorption. |
|
|
|
|
|
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. |
| Amoxicillin also has drug interactions. | |
|
|
See See |
|
|
|
|
|
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. |
|
|
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
|
|
|
|
|
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors |
|
|
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
|
|
|
|
|
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
|
|
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline |
|
|
|
|
|
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
|
|
An alternative confirmatory method should be considered to verify positive results. |
|
|
|
|
|
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
|
|
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole. |
| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
|
NC or 25% increase
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
|
| ↓ = Decreased (induces lamotrigine glucuronidation). |
||
| ↑ = Increased (inhibits lamotrigine glucuronidation). |
||
| ? = Conflicting data. |
||
|
|
Lamotrigine or Concomitant Drug |
|
|
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
|
|
? carbamazepine epoxide |
lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
|
|
|
|
|
|
|
|
|
|
|
approximately 40%. |
|
|
|
approximately 40%. |
|
|
|
approximately 40%. |
|
|
? valproate |
slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
|
|
||||
|
|
|
|
||
| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [
|
||
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) | Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate
|
||
| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)
|
||
| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated
|
Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets is co-administered with oral antidiabetic drugs [see Adverse Reactions (
|
||
| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) | To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin. | ||
| Cyclosporine | Use with caution (transient elevations in serum creatinine) | Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets is co-administered with cyclosporine. | ||
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) | The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anti-coagulant (for example, warfarin). | ||
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels | Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated. | ||
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [
|
||
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised. | ||
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. | ||
| Sildenafil | Use with caution Two-fold increase in exposure | Monitor for sildenafil toxicity [see
|
||
| Duloxetine | Avoid Use
Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity | ||
| Caffeine/Xanthine Derivatives | Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life | Ciprofloxacin tablets inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. | ||
|
|
||||
| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin tablets should be taken at least two hours before or six hours after Multivalent cation-containing products administration
|
Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels |
||
| Probenecid
|
Use with caution (interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin tablets serum levels)
|
Potentiation of ciprofloxacin tablets toxicity may occur.
|
||
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio
|
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| Name of the Concomitant Drug | Change in the Concentration of Ganciclovir or Concomitant Drug | Clinical Comment |
|---|---|---|
| Zidovudine |
↓ Ganciclovir ↑ Zidovudine |
Zidovudine and valganciclovir hydrochloride each have the potential to cause neutropenia and anemia |
| Probenecid |
↑ Ganciclovir |
Patients taking probenecid and valganciclovir hydrochloride should be monitored for evidence of ganciclovir toxicity |
| Mycophenolate Mofetil (MMF) |
↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) |
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase |
| Didanosine |
↓ Ganciclovir ↑ Didanosine |
Patients should be closely monitored for didanosine toxicity |
| NA – Not available/reported | ||||
|
|
||||
|
Concentration Increase |
Increase |
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|||
| DRUG | DESCRIPTION OF INTERACTION |
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. |
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. |
|
|
|
|
|
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome. |
|
|
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue |
|
|
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
|
|
|
|
|
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias. |
|
|
Concomitant use of pimozide and sertraline hydrochloride is contraindicated |
|
|
|
|
|
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome. |
|
|
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs |
|
|
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort |
|
|
|
|
|
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding. |
|
|
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio |
|
|
aspirin, clopidogrel, heparin, warfarin |
|
|
|
|
|
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma |
|
|
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted. |
|
|
warfarin |
|
|
|
|
|
Sertraline hydrochloride is a CYP2D6 inhibitor |
|
|
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued. |
|
|
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine |
|
|
|
|
|
Phenytoin is a narrow therapeutic index drug. sertraline hydrochloride may increase phenytoin concentrations. |
|
|
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed. |
|
|
phenytoin, fosphenytoin |
| a Total estrogens is the sum of conjugated and unconjugated estrogen. | ||||||
|
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|||||
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|
|
| Estradiol | 0.037 ± 0.048 |
12.7 ± 9.1 |
0.676 ± 0.737 |
0.030 ± 0.032 |
17.32 ± 1.21 |
0.561 ± 0.572 |
| Estrone Total a |
3.68 ± 1.55 |
10.6 ± 6.8 |
61.3 ± 26.36 |
4.93 ± 2.07 |
7.5 ± 3.8 |
85.9 ± 41.2 |
| Equilin Total a |
2.27 ± 0.95 |
6.0 ± 4.0 |
28.8 ± 13.0 |
3.22 ± 1.13 |
5.3 ± 2.6 |
38.1 ± 20.2 |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , )
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Avoid atorvastatin
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| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
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Do not exceed 20 mg atorvastatin daily
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| HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)
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Do not exceed 40 mg atorvastatin daily |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
|
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| Antacids, sucralfate, multivitamins, and other products containing multivalent cations | Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin | Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
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| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Known CYP2D6 Poor Metabolizers |
Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors |
Administer a quarter of usual dose |
| Strong CYP2D6 or CYP3A4 inhibitors |
Administer half of usual dose |
| Strong CYP2D6 and CYP3A4 inhibitors |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers |
Double usual dose over 1 to 2 weeks |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
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? carbamazepine epoxide |
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? valproate |
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| Estrogen-containing oral
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine
|
Decreased lamotrigine levels
approximately 50%. |
|
|
↓ levonorgestrel
|
Decrease in levonorgestrel component by 19%.
|
| Carbamazepine (CBZ) and
CBZ epoxide |
↓ lamotrigine
|
Addition of carbamazepine decreases lamotrigine
concentration approximately 40%. |
|
|
? CBZ epoxide
|
May increase CBZ epoxide levels
|
| Phenobarbital/Primidone
|
↓ lamotrigine
|
Decreased lamotrigine
concentration approximately 40%. |
| Phenytoin (PHT)
|
↓ lamotrigine
|
Decreased lamotrigine
concentration approximately 40% |
| Rifampin
|
↓ lamotrigine
|
Decreased lamotrigine AUC
approximately 40% |
| Valproate
|
↑ lamotrigine
|
Increased lamotrigine concentrations slightly
more than 2-fold. |
|
|
? valproate
|
Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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• Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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• In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
|
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• During concomitant use of naproxen delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see |
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NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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| Drug or Drug Class | Effect | Clinical Comment |
|---|---|---|
| ↑ Indicates increase. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine delayed-release capsules b |
||
|
Drugs that may cause pancreatic toxicity |
↑ risk of pancreatitis |
Use only with extreme caution.a |
|
Neurotoxic drugs |
↑ risk of neuropathy |
Use with caution.b |
| Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment |
|---|---|---|
|
antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate) |
↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake) |
The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA. |
|
fluconazole itraconazole ketoconazole posaconazole voriconazole |
↑ rilpivirine ↓ ketoconazole |
Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA. |
|
cimetidine famotidine nizatidine ranitidine |
↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) ↓ rilpivirine (famotidine taken 2 hours before rilpivirine) |
The combination of COMPLERA and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA. |
|
clarithromycin erythromycin telithromycin |
↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin |
Concomitant use of COMPLERA with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered. |
|
methadone |
↓ R(–) methadone ↓ S(+) methadone ↔ rilpivirine ↔ methadone |
No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
|
albuterol, systemic and inhaled |
mebendazole |
|
amoxicillin |
medroxyprogesterone |
|
ampicillin, with or without |
methylprednisolone |
|
sulbactam |
metronidazole |
|
atenolol |
metoprolol |
|
azithromycin |
nadolol |
|
caffeine, dietary ingestion |
nifedipine |
|
cefaclor |
nizatidine |
|
co-trimoxazole (trimethoprim and sulfamethoxazole) |
norfloxacin |
|
ofloxacin |
|
|
diltiazem |
omeprazole |
|
dirithromycin |
prednisone, prednisolone |
|
enflurane |
ranitidine |
|
famotidine |
rifabutin |
|
felodipine |
roxithromycin |
|
finasteride |
Sorbitol (purgative doses do not inhibit |
|
hydrocortisone |
theophylline absorption) |
|
isoflurane |
sucralfate |
|
isoniazid |
terbutaline, systemic |
|
isradipine |
terfenadine |
|
influenza vaccine |
tetracycline |
|
ketoconazole |
tocainide |
|
lomefloxacin |
|
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. | |
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|
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. |
|
|
o Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( |
|
|
o Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see clinical Pharmacology ( |
|
|
o There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. |
|
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Rilpivirine-containing products: Concomitant use with omeprazole delayed-release capsule is contraindicated [see Contraindications ( |
|
|
Atazanavir: Avoid concomitant use with omeprazole delayed-release capsules. See prescribing information for atazanavir for dosing information. |
|
|
Nelfinavir: Avoid concomitant use with omeprazole delayed-release capsules. See prescribing information for nelfinavir. |
|
|
Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. |
|
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Other antiretrovirals: See prescribing information for specific antiretroviral drugs. |
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Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
|
|
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. |
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Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( |
|
|
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. |
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Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( |
|
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Avoid concomitant use with omeprazole delayed-release capsules. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( |
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Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( |
|
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Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. |
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Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( |
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Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. |
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Potential for increased exposure of phenytoin. |
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Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. |
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Increased exposure of diazepam [see Clinical Pharmacology ( |
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Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
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Potential for increased exposure of digoxin [see Clinical Pharmacology ( |
|
|
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. |
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Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
|
|
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole delayed-release capsules and MMF. Use omeprazole delayed-release capsules with caution in transplant patients receiving MMF [see Clinical Pharmacology ( |
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Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. |
|
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See See |
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|
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 |
|
|
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
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Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( |
|
|
Temporarily stop omeprazole delayed-release capsules treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
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|
|
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
|
|
Temporarily stop omeprazole delayed-release capsules treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( |
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|
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
|
|
An alternative confirmatory method should be considered to verify positive results. |
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|
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
|
|
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole delayed-release capsules. |
| Interacting Drug | Interaction |
|---|---|
| Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). | QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades des Pointes. Avoid concomitant use ( |
| Other antimalarials (e.g., halofantrine, mefloquine). | ECG abnormalities including QT prolongation. Avoid concomitant use ( |
| CYP3A4 inducers or inhibitors | Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( |
| CYP3A4 and CYP2D6 substrates | Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( |
| Digoxin | Increased digoxin plasma concentration ( |
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|---|
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Hepatitis C protease inhibitor (boceprevir) |
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||
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| Tizanidine |
Contraindicated |
Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline |
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. |
| Drugs Known to Prolong QT Interval |
Avoid Use |
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs |
Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin |
Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine |
Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs |
Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate |
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole |
Use with caution |
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin |
| Clozapine |
Use with caution |
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs |
Use with caution |
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing. |
| Sildenafil |
Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine |
Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
|
|
||
| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Probenecid |
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
|
|
|
|
|
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
|
|
Reserve concomitant prescribing of these drugs for use in patients
for whom alternative treatment options are inadequate. Limit dosages
and durations to the minimum required. Follow patients closely for
signs of respiratory depression and sedation |
|
|
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
|
|
|
|
|
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
|
|
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DILAUDID Oral Solution or DILAUDID Tablets if serotonin syndrome is suspected. |
|
|
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
|
|
|
|
|
MAOI interactions with opioids may manifest as serotonin syndrome
or opioid toxicity (e.g., respiratory depression, coma) If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. |
|
|
The use of DILAUDID Oral Solution or DILAUDID Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
|
|
phenelzine, tranylcypromine, linezolid |
|
|
|
|
|
May reduce the analgesic effect of DILAUDID Oral Solution or DILAUDID Tablets and/or precipitate withdrawal symptoms. |
|
|
Avoid concomitant use. |
|
|
butorphanol, nalbuphine, pentazocine, buprenorphine, |
|
|
|
|
|
Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
|
|
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DILAUDID Oral Solution or DILAUDID Tablets and/or the muscle relaxant as necessary. |
|
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|
|
|
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
|
|
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
|
|
|
|
|
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
|
|
Monitor patients for signs of urinary retention or reduced gastric motility when DILAUDID Oral Solution or DILAUDID Tablets is used concomitantly with anticholinergic drugs. |
| |
|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Concomitant Drug Name or Drug Class | Clinical Rationale | Clinical Recommendation |
|---|---|---|
| Acidifying and Alkalinizing Agents | Ascorbic acid and other agents that acidify urine increase urinary excretion and decrease the half-life of amphetamine. Sodium bicarbonate and other agents that alkalinize urine decrease urinary excretion and extend the half-life of amphetamine. | Adjust the dose accordingly |
|
|
|
| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases theophylline clearance at allopurinol doses ≥600 mg/day. | 25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-stateserum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P4501A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
| * Refer to | ||
| ** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed. | ||
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| Concomitant Drug
|
Effect on Concentration of
Lamotrigine or Concomitant Drug |
Clinical Comment
|
| Estrogen-containing oral
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine
↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide
|
↓ lamotrigine
? carbamazepine epoxide |
Addition of carbamazepine decreases
lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 50%.
|
| Atazanavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine AUC approximately 32%.
|
| Phenobarbital/Primidone
|
↓ lamotrigine
|
Decreased lamotrigine concentration
approximately 40%. |
| Phenytoin
|
↓ lamotrigine
|
Decreased lamotrigine concentration
approximately 40%. |
| Rifampin
|
↓ lamotrigine
|
Decreased lamotrigine AUC
approximately 40%. |
| Valproate
|
↑ lamotrigine
? valproate |
Increased lamotrigine concentrations
slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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| albuterol, systemic and inhaled | hydrocortisone | ofloxacin |
| amoxicillin | isoflurane | omeprazole |
| ampicillin, with or without | isoniazid | prednisone, prednisolone |
| sulbactam | isradipine | ranitidine |
| atenolol | influenza vaccine | rifabutin |
| azithromycin | ketoconazole | roxithromycin |
| caffeine, dietary ingestion | lomefloxacin | sorbitol |
| cefaclor | mebendazole | (purgative doses do |
| co-trimoxazole (trimethoprim | medroxyprogesterone | not inhibit theophylline |
| and sulfamethoxazole) | methylprednisolone | absorption) |
| diltiazem | metronidazole | sucralfate |
| dirithromycin | metoprolol | terbutaline,systemic |
| enflurane | nadolol | terfenadine |
| famotidine | nifedipine | tetracycline |
| felodipine | nizatidine | tocainide |
| finasteride | norfloxacin | |
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If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
|
The concomitant use of aripiprazole tablets with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole tablets alone
|
With concomitant use of aripiprazole tablets with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole tablets dosage
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| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
|
The concomitant use of aripiprazole tablets and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole tablets alone
|
With concomitant use of aripiprazole tablets with a strong CYP3A4 inducer, consider increasing the aripiprazole tablets dosage
|
|
Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
|
Monitor blood pressure and adjust dose accordingly
|
|
Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that
observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly.
|
|
|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
| Concomitant Drug Class: Drug Name | Effect | Clinical Comment |
|---|---|---|
|
|
||
| Protease inhibitor: atazanavir |
↓atazanavir concentration ↑ tenofovir concentration |
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. |
| Protease inhibitor: fosamprenavir calcium |
↓ amprenavir concentration | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: indinavir |
↓ indinavir concentration | The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Protease inhibitor: lopinavir/ritonavir |
↓ lopinavir concentration ↑ tenofovir concentration |
A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). |
| Protease inhibitor: ritonavir |
↑ ritonavir concentration ↑ efavirenz concentration |
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. |
| Protease inhibitor: saquinavir |
↓ saquinavir concentration | Should not be used as sole protease inhibitor in combination with ATRIPLA. |
| NRTI: didanosine |
↑ didanosine concentration | Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. |
|
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||
| Anticoagulant: warfarin |
↑ or ↓ warfarin concentration | Plasma concentrations and effects potentially increased or decreased by efavirenz. |
| Anticonvulsants: carbamazepine |
↓ carbamazepine concentration ↓ efavirenz concentration |
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. |
| phenytoin phenobarbital |
↓ anticonvulsant concentration ↓ efavirenz concentration |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressant: sertraline |
↓ sertraline concentration | Increases in sertraline dose should be guided by clinical response. |
| Antifungals: itraconazole |
↓ itraconazole concentration ↓ hydroxy-itraconazole concentration |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| ketoconazole | ↓ ketoconazole concentration | Drug interaction studies with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. |
| Anti-infective: clarithromycin |
↓ clarithromycin concentration ↑ 14-OH metabolite concentration |
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA. |
| Antimycobacterial: rifabutin |
↓ rifabutin concentration | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| Antimycobacterial: rifampin |
↓ efavirenz concentration |
Clinical significance of reduced efavirenz concentration is unknown. Dosing recommendations for concomitant use of ATRIPLA and rifampin have not been established. |
| Calcium channel blockers: diltiazem |
↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration |
Diltiazem dose adjustments should be guided by clinical response (refer to the prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. |
| Others (e.g., felodipine, nicardipine, nifedipine, verapamil) | ↓ calcium channel blocker | No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the prescribing information for the calcium channel blocker). |
| HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin |
↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: | ||
| Oral: Ethinyl estradiol/Norgestimate |
↓ active metabolites of norgestimate | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant: Etonogestrel |
↓ etonogestrel | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immuno-suppressant | Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. |
| Narcotic analgesic: methadone |
↓ methadone concentration | Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
| *Change relative to reference
|
|||||
| Coadministered Drug
|
Dosing Schedule
|
Effect on Active Moiety
(Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose
Recommendation |
||
| Coadministered Drug
|
Risperidone
|
AUC
|
Cmax
|
||
| Enzyme (CYP2D6) inhibitors
|
|
|
|
|
|
| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice daily
|
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
-
|
Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day
|
4 mg/day
|
1.6
|
-
|
||
| 40 mg/day
|
4 mg/day
|
1.8
|
-
|
||
| Enzyme (CYP3A/ PgP inducers) Inducers
|
|
|
|
|
|
| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) inhibitors
|
|
|
|
|
|
| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not needed
|
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not needed
|
| Erythromycin
|
500 mg four times daily
|
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not needed
|
| Other Drugs
|
|
|
|
|
|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not Needed
|
| DRUG | DISCRIPTION OF INTERACTION |
|---|---|
| Heparin | Salicylate decreases platelet adhesiveness and inteferes with hemostasis in heparin treated patients. |
| Pyrazinamide | Inhibits pyrazinamide induced hyperuricemia. |
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. |
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Norepinephrine Dopamine |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours | |
| Allopurinol | |
25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentratrions of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance in unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increase theophylline clearance. | 20% increase |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% increase |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects;possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% increase |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
| |
|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| 1nc denotes a mean change of less than 10% | ||||
| 2Pediatrics | ||||
| 3Mean increase in adults at high oxcarbazepine doses | ||||
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[CI: 17% decrease, 57% decrease] |
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[CI: 2% increase, 24% increase] |
[CI: 12% decrease, 51% decrease] |
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|
>1200 to 2400 |
up to 40% increase3 [CI: 12% increase, 60% increase] |
[CI: 3% decrease, 48% decrease] |
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[CI: 13% decrease, 40% decrease] |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
| * Results based on ** Results based on *** Results based on **** Non-Steroidal Anti-Inflammatory Drug ***** Non-Nucleoside Reverse Transcriptase Inhibitors |
||
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|
| Sirolimus* (CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin* (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (400 mg q24h)** (CYP3A4 Inhibition) Efavirenz (300 mg q24h)** (CYP3A4 Inhibition) |
Significantly Increased Slight Increase in AUCτ |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)** |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ
Slight Decrease in Ritonavir Cmax and AUCτ |
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
|
| Cyclosporine* (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax
|
When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone*** (CYP3A4 Inhibition) |
Increased |
Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) |
Increased |
Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| Alfentanil (CYP3A4 Inhibition) |
Significantly Increased |
Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ |
| Oxycodone (CYP3A4 Inhibition) |
Significantly Increased |
Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| NSAIDs**** including. ibuprofen and diclofenac (CYP2C9 Inhibition) |
Increased |
Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ |
| Tacrolimus* (CYP3A4 Inhibition) |
Significantly Increased |
When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin* (CYP2C9 Inhibition) |
Significantly Increased |
Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** |
Increased |
Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin* (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased |
Monitor PT or other suitable anti- coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole* (CYP2C19/3A4 Inhibition) |
Significantly Increased |
When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment for indinavir when coadministered with voriconazole Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors |
| Other NNRTIs***** (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
|
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
|
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
|
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
| Everolimus (CYP3A4 Inhibition) |
Not Studied |
Concomitant administration of voriconazole and everolimus is not recommended. |
| Name of the Concomitant Drug | Change in the Concentration of Ganciclovir or Concomitant Drug | Clinical Comment |
|---|---|---|
| Didanosine | ↑ Didanosine |
|
| Zidovudine | ↓ Ganciclovir ↑ Zidovudine |
Dose reduction or interruption may be needed because both zidovudine and ganciclovir have the potential to cause neutropenia and anemia. Monitor with frequent tests of white blood cell counts with differential and hemoglobin levels. |
| Probenecid | ↑ Ganciclovir | GANCICLOVIR INJECTION dose may need to be reduced. Monitor for evidence of ganciclovir toxicity. |
| Imipenem-cilastatin | Unknown |
|
| Cyclosporine or amphotericin B | Unknown | Monitor renal function when GANCICLOVIR INJECTION is co-administered with cyclosporine or amphotericin B because of potential increase in serum creatinine [see Warnings and Precautions ( |
| Dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulfamethoxazole combinations or other nucleoside analogues | Unknown | Co-administration with GANCICLOVIR INJECTION should be considered only if the potential benefits are judged to outweigh the risks because of potential additive toxicity. |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety(Risperidone + 9- Hydroxy- Risperidone (Ratio*) | Risperidone DoseRecommendation | ||
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6)Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Donot exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | Re-evaluate dosing. Do not exceed 8 mg/day | |
| Enzyme (CYP3A/PgP inducers)Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards.Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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| ciprofloxacin | melphalan | Azapropazon | cimetidine |
| gentamicin | Colchicine | ranitidine | |
| tobramycin |
|
Diclofenac | |
| vancomycin | amphotericin B | Naproxen |
|
| trimethoprim with sulfamethoxazole | ketoconazole | Sulindac | tacrolimus |
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| fibric acid derivatives (e.g., bezafibrate, fenofibrate) |
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| methotrexate |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| % Change from Plavix (300 mg/75 mg) alone | ||||||
|---|---|---|---|---|---|---|
| Plavix plus | Cmax (ng/mL) | AUC | Platelet Inhibition |
|||
| Day 1 | Day 5 | Day 1 | Day 5 |
Day 1 | Day 5 | |
| Omeprazole |
↓46% | ↓42% | ↓45% | ↓40% | ↓39% | ↓21% |
| Pantoprazole 80 mg | ↓24% | ↓28% | ↓20% | ↓14% | ↓15% | ↓11% |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. The depressant effects of morphine are potentiated by the presence of other CNS depressants. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression. |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, psychotropic drugs, antihistamines, neuroleptics, other opioids, alcohol |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue INFUMORPH if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) |
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phenelzine, tranylcypromine, linezoli |
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May reduce the analgesic effect of INFUMORPH and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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Butorphanol, nalbuphine, pentazocine, buprenorphine. |
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Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of INFUMORPH and/or the muscle relaxant as necessary |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation,which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when INFUMORPH is used concomitantly with anticholinergic drugs. |
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| Clinical Impact: | Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
| Intervention: | Monitor patients with concomitant use of oxaprozin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see |
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| Clinical Impact: | Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see |
| Intervention: | Concomitant use of oxaprozin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see |
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| Clinical Impact: | NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
| Intervention: | During concomitant use of oxaprozin and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of oxaprozin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see |
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| Clinical Impact: | Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
| Intervention: | During concomitant use of oxaprozin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see |
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| Clinical Impact: | The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
| Intervention: | During concomitant use of oxaprozin and digoxin, monitor serum digoxin levels. |
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| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
| Intervention: | During concomitant use of oxaprozin and lithium, monitor patients for signs of lithium toxicity. |
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| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate. |
| Intervention: | During concomitant use of oxaprozin and methotrexate, monitor patients for methotrexate toxicity. |
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| Clinical Impact: | Concomitant use of oxaprozin and cyclosporine may increase cyclosporine’s nephrotoxicity. |
| Intervention: | During concomitant use of oxaprozin and cyclosporine, monitor patients for signs of worsening renal function. |
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| Clinical Impact: | Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see |
| Intervention: | The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended. |
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| Clinical Impact: | Concomitant use of oxaprozin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
| Intervention: | During concomitant use of oxaprozin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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| Clinical Impact: |
Concomitant use of corticosteroids with oxaprozin may increase the risk of GI ulceration or bleeding. |
| Intervention: |
Monitor patients with concomitant use of oxaprozin with corticosteroids for signs of bleeding [see |
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| Clinical Impact: |
While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control. |
| Intervention: | During concomitant use of oxaprozin and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy. |
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| Known CYP2D6 Poor Metabolizers |
Administer half of usual dose |
| KnownCYP2D6Poor Metabolizersand strongCYP3A4 inhibitors |
Administer a quarter of usualdose |
| StrongCYP2D6 or CYP3A4inhibitors |
Administerhalf of usual dose |
| StrongCYP2D6andCYP3A4 inhibitors |
Administer a quarter of usualdose |
| StrongCYP3A4inducers |
Double usual doseover 1 to 2 weeks |
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| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| Specific Drugs Reported | |||
| also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone |
cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate |
6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone |
propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage |
|
albuterol, systemic and inhaled |
mebendazole |
|
amoxicillin |
medroxyprogesterone |
|
ampicillin, with or without |
methylprednisolone |
|
sulbactam |
metronidazole |
|
atenolol |
metoprolol |
|
azithromycin |
nadolol |
|
caffeine, dietary ingestion |
nifedipine |
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cefaclor |
nizatidine |
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co-trimoxazole (trimethoprim and sulfamethoxazole) |
norfloxacin |
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ofloxacin |
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diltiazem |
omeprazole |
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dirithromycin |
prednisone, prednisolone |
|
enflurane |
ranitidine |
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famotidine |
rifabutin |
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felodipine |
roxithromycin |
|
finasteride |
Sorbitol (purgative doses do not inhibit |
|
hydrocortisone |
theophylline absorption) |
|
isoflurane |
sucralfate |
|
isoniazid |
terbutaline, systemic |
|
isradipine |
terfenadine |
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influenza vaccine |
tetracycline |
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ketoconazole |
tocainide |
|
lomefloxacin |
|
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
|---|---|
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
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If concomitant use is warranted, carefully observe the patient during treatment initiation. Discontinue Morphine Sulfate Injection, (Auto-Injector) if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) |
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Do not use Morphine Sulfate Injection, (Auto-Injector) in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of Morphine Sulfate Injection, (Auto-Injector) and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Morphine sulfate may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the frequency of injections of Morphine Sulfate Injection, (Auto-Injector) and/or decrease the dose of the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Injection, (Auto-Injector) is used concomitantly with anticholinergic drugs. |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone
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Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding
Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis
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During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
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Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
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During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
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Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
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During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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↑ Nevirapine |
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↑ Nevirapine |
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↑ Nevirapine |
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A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
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↓Nelfinavir Cmin |
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Etravirine Rilpivirine |
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↑ 14-OH clarithromycin |
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Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
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Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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↓ Norethindrone |
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| Tizanidine | Contraindicated | Concomitant administration of tizanidine and Ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [
|
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) | Concurrent administration of Ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate.
|
| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)
|
| Oral antidiabetic drugs
|
Use with caution Glucose-lowering effect potentiated | Hypoglycemia sometimes severe has been reported when Ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when Ciprofloxacin is co-administered with oral antidiabetic drugs.
|
| Phenytoin
|
Use with caution Altered serum levels of phenytoin (increased and decreased) | To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon Ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of Ciprofloxacin with phenytoin. |
| Cyclosporine
|
Use with caution (transient elevations in serum creatinine) | Monitor renal function (in particular serum creatinine) when Ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs
|
Use with caution (Increase in anticoagulant effect) | The risk may vary with the underlying infection, age and general status of the patient so that the contribution of Ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of Ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate
|
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels | Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant Ciprofloxacin therapy is indicated. |
| Ropinirole
|
Use with caution
|
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with Ciprofloxacin
|
| Clozapine
|
Use with caution
|
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with Ciprofloxacin are advised. |
| NSAIDs
|
Use with caution
|
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil
|
Use with caution Two-fold increase in exposure | Monitor for sildenafil toxicity (
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| Duloxetine
|
Avoid Use
Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity. |
| Caffeine/Xanthine
Derivatives |
Use with caution
Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
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| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration
|
Decrease Ciprofloxacin absorption, resulting in lower serum and urine levels
|
| Probenecid | Use with caution (interferes with renal tubular secretion of Ciprofloxacin and increases Ciprofloxacin serum levels) | Potentiation of Ciprofloxacin toxicity may occur. |
| *Change relative to reference
|
|||||
| Coadministered Drug
|
Dosing Schedule
|
Effect on Active Moiety
(Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose
Recommendation |
||
| Coadministered Drug
|
Risperidone
|
AUC
|
Cmax
|
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| Enzyme (CYP2D6) inhibitors
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| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice daily
|
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
-
|
Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day
|
4 mg/day
|
1.6
|
-
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| 40 mg/day
|
4 mg/day
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1.8
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-
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| Enzyme (CYP3A/ PgP inducers) Inducers
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| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
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0.55
|
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) inhibitors
|
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| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
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1.4
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Dose adjustment not needed
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| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not needed
|
| Erythromycin
|
500 mg four times daily
|
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not needed
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| Other Drugs
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| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
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1.2
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1.1
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Dose adjustment not Needed
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| Concomitant Drug
|
Effect on Concentration of
Lamotrigine or Concomitant Drug |
Clinical Comment
|
| Estrogen-containing oral
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine
↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide
|
↓ lamotrigine
? carbamazepine epoxide |
Addition of carbamazepine decreases
lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 50%.
|
| Atazanavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine AUC approximately 32%.
|
| Phenobarbital/Primidone
|
↓ lamotrigine
|
Decreased lamotrigine concentration
approximately 40%. |
| Phenytoin
|
↓ lamotrigine
|
Decreased lamotrigine concentration
approximately 40%. |
| Rifampin
|
↓ lamotrigine
|
Decreased lamotrigine AUC
approximately 40%. |
| Valproate
|
↑ lamotrigine
? valproate |
Increased lamotrigine concentrations
slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| 1 nc denotes a mean change of less than 10% | ||||
| 2 Pediatrics | ||||
| 3 Mean increase in adults at high oxcarbazepine doses | ||||
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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See |
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| Clinical Impact: | Concomitant use of LATUDA with strong CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of LATUDA alone [ |
| Intervention: | LATUDA should not be used concomitantly with strong CYP3A4 inhibitors [ |
| Examples: | Ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil |
|
|
|
| Clinical Impact: | Concomitant use of LATUDA with moderate CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of LATUDA alone [ |
| Intervention: | LATUDA dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 [ |
| Examples: | Diltiazem, atazanavir, erythromycin, fluconazole, verapamil |
|
|
|
| Clinical Impact: | Concomitant use of LATUDA with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of LATUDA alone [ |
| Intervention: | LATUDA should not be used concomitantly with strong CYP3A4 inhibitors [ |
| Examples: | Rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine |
|
|
|
| Clinical Impact: | Concomitant use of LATUDA with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of LATUDA alone [ |
| Intervention: | LATUDA dose should be increased when used concomitantly with moderate inducers of CYP3A4 [ |
| Examples: | Bosentan, efavirenz, etravirine, modafinil, nafcillin |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, Amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
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Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death |
|
|
Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. |
|
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Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted |
|
|
A temporary withdrawal of Rabeprazole Sodium Delayed-Release Tablets may be considered in some patients receiving high dose methotrexate administration. |
|
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|
Potential for increased exposure of digoxin |
|
|
Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. |
|
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|
Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity. |
|
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|
See |
|
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|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| albuterol, systemic and inhaled | diltiazem | medroxyprogesterone | roxithromycin |
| dirithromycin | methylprednisolone | Sorbitol (purgative doses do not inhibit theophylline absorption) |
|
| amoxicillin | enflurane | metronidazole | |
| ampicillin, with or without sulbactam | famotidine | metoprolol | |
| felodipine | nadolol | ||
| finasteride | nifedipine | ||
| atenolol | hydrocortisone | nizatidine | sucralfate |
| azithromycin | isoflurane | norfloxacin | terbutaline, systemic |
| caffeine, dietary ingestion | isoniazid | ofloxacin | terfenadine |
| isradipine | omeprazole | tetracycline | |
| cefaclor | influenza vaccine | prednisone, prednisolone |
tocainide |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | ketoconazole | ||
| lomefloxacin | ranitidine | ||
| mebendazole | rifabutin | ||
| * Refer to |
|||
|
|
|
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|
|
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
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|
| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
|
|
|
| Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Drug Class | Examples of Drugs Within Class |
|---|---|
| Antiarrhythmics | Disopyramide, mexiletine, quinidine, tocainide |
| Antibiotics | Chloramphenicol, clarithromycin, dapsone, doxycycline; Fluoroquinolones (such as ciprofloxacin) |
| Oral Anticoagulants | Warfarin |
| Anticonvulsants | Phenytoin |
| Antimalarials | Quinine |
| Azole Antifungals | Fluconazole, itraconazole, ketoconazole |
| Antipsychotics | Haloperidol |
| Barbiturates | Phenobarbital |
| Benzodiazepines | Diazepam |
| Beta-Blockers | Propanolol |
| Calcium Channel Blockers | Diltiazem, nifedipine, verapamil |
| Cardiac Glycoside Preparations | Digoxin |
| Corticosteroids | Prednisone |
| Fibrates | Clofibrate |
| Oral Hypoglycemics | Sulfonylureas (e.g., glyburide, glipizide) |
| Hormonal Contraceptives/ Progestins | Ethinyl estradiol, levonorgestrel |
| Immunosuppressants | Cyclosporine, tacrolimus |
| Methylxanthines | Theophylline |
| Narcotic analgesics | Methadone |
| Phophodiesterase-5 (PDE-5) Inhibitors | Sildenafil |
| Thyroid preparations | Levothyroxine |
| Tricyclic antidepressants | Amitriptyline, nortriptyline |
|
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||
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|
|
||
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
|
|
||
|
|
||
|
|
||
| Concomitant Drug
|
Effect on Concentration of
Lamotrigine or Concomitant Drug |
Clinical Comment
|
| Estrogen-containing oral
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine
↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide
|
↓ lamotrigine
? carbamazepine epoxide |
Addition of carbamazepine decreases
lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 50%.
|
| Atazanavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine AUC approximately 32%.
|
| Phenobarbital/Primidone
|
↓ lamotrigine
|
Decreased lamotrigine concentration
approximately 40%. |
| Phenytoin
|
↓ lamotrigine
|
Decreased lamotrigine concentration
approximately 40%. |
| Rifampin
|
↓ lamotrigine
|
Decreased lamotrigine AUC
approximately 40%. |
| Valproate
|
↑ lamotrigine
? valproate |
Increased lamotrigine concentrations
slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
|
|
|||
|
|
|
|
|
| Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide |
Not Recommended |
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
|
| Digoxin |
Use With Caution |
|
|
| Oral Anticoagulants: Warfarin |
Use With Caution |
|
|
| Antiepileptics: Carbamazepine |
Use With Caution |
|
|
| Antifungals: Itraconazole |
Use With Caution |
|
|
| Fluconazole |
No Dose Adjustment |
|
|
| Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function) |
Contraindicated Use With Caution |
|
|
| Antipsychotics: Pimozide Quetiapine |
Contraindicated |
|
|
| Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity) |
Use With Caution |
|
|
| Antivirals: Atazanavir |
Use With Caution |
|
|
| Saquinavir (in patients with decreased renal function) |
|
|
|
| Ritonavir Etravirine |
|
|
|
| Maraviroc |
|
|
|
| Boceprevir (in patients with normal renal function) Didanosine |
No Dose Adjustment |
|
|
| Zidovudine |
|
|
|
| Calcium Channel Blockers: Verapamil |
Use With Caution |
|
|
| Amlodipine Diltiazem |
|
|
|
| Nifedipine |
|
|
|
| Ergot Alkaloids: Ergotamine Dihydroergotamine |
Contraindicated |
|
|
| Gastroprokinetic Agents: Cisapride |
Contraindicated |
|
|
| HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin |
Contraindicated |
|
|
| Atorvastatin Pravastatin |
Use With Caution |
|
|
| Fluvastatin |
No Dose Adjustment |
|
|
| Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone |
Use With Caution |
|
|
| Insulin |
|
|
|
| Immunosuppressants: Cyclosporine |
Use With Caution |
|
|
| Tacrolimus |
|
|
|
| Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil |
Use With Caution |
|
|
| Proton Pump Inhibitors: Omeprazole |
No Dose Adjustment |
|
|
| Xanthine Derivatives: Theophylline |
Use With Caution |
|
|
| Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam |
Use With Caution |
|
|
| Alprazolam Triazolam |
|
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
|
| Temazepam Nitrazepam Lorazepam |
No Dose Adjustment |
|
|
| Cytochrome P450 Inducers: Rifabutin |
Use With Caution |
|
|
| Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution |
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. |
|
| Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: |
|
|
|
| Hexobarbital Phenytoin Valproate |
Use With Caution |
There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. |
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| Antifungals: Itraconazole |
Use With Caution |
|
|
| Antivirals: Atazanavir |
Use With Caution |
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to |
|
| Ritonavir (in patients with decreased renal function) |
|
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. |
|
| Saquinavir (in patients with decreased renal function) |
|
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| Etravirine |
|
|
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| Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function) |
No Dose Adjustment |
|
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| Proton Pump Inhibitors: Omeprazole |
Use With Caution |
|
|
| Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine |
Use With Caution |
Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above). |
|
| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin |
NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxide |
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Specific Drugs Reported | |||
| also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide |
diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine |
lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone |
propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton |
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| Phenytoin
|
NC or 25% increase
a
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
b
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
|
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||
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|
| Antrum | 10.48 ± 2.01 (n = 5) | 19.96 ± 4.71 (n = 5) |
| Fundus | 20.81 ± 7.64 (n = 5) | 24.25 ± 6.37 (n = 5) |
| Mucus | 4.15 ± 7.74 (n = 4) | 39.29 ± 32.79 (n = 4) |
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| Antiarrhythmics: |
||
| Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide |
Not Recommended |
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
| Digoxin | Use With Caution |
|
| Oral Anticoagulants: |
||
| Warfarin | Use With Caution |
|
| Antiepileptics: |
||
| Carbamazepine | Use With Caution |
|
| Antifungals: |
||
|
|
Use With Caution |
|
| Fluconazole | No Dose Adjustment |
|
| Anti-Gout Agents: |
||
| Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function) |
Contraindicated Use With Caution |
|
| Antipsychotics: |
||
| Pimozide | Contraindicated |
|
| Quetiapine |
|
|
| Antispasmodics: |
||
| Tolterodine (patients deficient in CYP2D6 activity) | Use With Caution |
|
| Antivirals: |
||
| Atazanavir | Use With Caution |
|
| Saquinavir (in patients with decreased renal function) |
|
|
| Ritonavir Etravirine |
|
|
| Maraviroc |
|
|
| Boceprevir (in patients with normal renal function) Didanosine |
No Dose Adjustment |
|
| Zidovudine |
The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated. |
|
| Calcium Channel Blockers: |
||
| Verapamil | Use With Caution |
|
| Amlodipine Diltiazem |
|
|
| Nifedipine |
|
|
| Ergot Alkaloids: |
||
| Ergotamine Dihydroergotamine |
Contraindicated |
|
| Gastroprokinetic Agents: |
||
| Cisapride | Contraindicated |
|
| HMG-CoA Reductase Inhibitors: |
||
| Lovastatin Simvastatin |
Contraindicated |
|
| Atorvastatin Pravastatin |
Use With Caution | |
| Fluvastatin |
No Dose Adjustment |
|
| Hypoglycemic Agents: |
||
| Nateglinide Pioglitazone Repaglinide Rosiglitazone |
Use With Caution |
|
| Insulin |
|
|
| Immunosuppressants: |
||
| Cyclosporine | Use With Caution |
|
| Tacrolimus |
|
|
| Phosphodiesterase inhibitors: |
||
| Sildenafil Tadalafil Vardenafil |
Use With Caution |
|
| Proton Pump Inhibitors: |
||
| Omeprazole | No Dose Adjustment |
|
| Xanthine Derivatives: |
||
| Theophylline | Use With Caution |
|
| Triazolobenzodiazepines and Other Related Benzodiazepines: |
||
| Midazolam | Use With Caution |
|
| Alprazolam Triazolam |
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
|
| Temazepam Nitrazepam Lorazepam |
No Dose Adjustment |
|
| Cytochrome P450 Inducers: |
||
|
|
Use With Caution |
|
| Other Drugs Metabolized by CYP3A: |
||
| Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution | There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. |
| Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: |
||
| Hexobarbital Phenytoin Valproate |
Use With Caution | There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. |
|
|
||
|
|
|
|
| Antifungals: |
||
|
|
Use With Caution | Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also |
| Antivirals: |
||
|
|
Use With Caution |
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to |
|
|
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. |
|
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|
|
|
|
|
|
| Saquinavir (in patients with normal renal function) | No Dose Adjustment | |
| Ritonavir (in patients with normal renal function) |
||
| Proton Pump Inhibitors: |
||
|
|
Use With Caution |
|
| Miscellaneous Cytochrome P450 Inducers: |
||
| Efavirenz Nevirapine Rifampicin Rifapentine |
Use With Caution | Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see |
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Sulfonylureas | Hypoglycemia potentiated. | ||
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. | ||
| Oral Anticoagulants | Increased bleeding. | ||
|
|
|||
| DRUG | DESCRIPTION OF INTERACTION | ||
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. | ||
| Acidifying Agents | Increases plasma salicylate levels. | ||
| Alkanizing Agents | Decreased plasma salicylate levels. | ||
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|
|||
| DRUG | DESCRIPTION OF INTERACTION | ||
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. | ||
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. | ||
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. | ||
| The following alterations of laboratory tests have been reported during salicylate therapy: | |||
| LABORATORY TESTS | EFFECT OF SALICYLATES | ||
| Thyroid Function | Decreased PBI; increased t3 uptake. | ||
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). | ||
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. | ||
| Acetone ketone bodies | False positive FeCI3 in Gerhardt reaction; red color persists with boiling. | ||
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. | ||
| Vanilmandelic acid | False reduced values. | ||
| Uric Acid | May increase or decrease depending on dose. | ||
| Prothrombin | Decreased levels; slightly increased prothrombin time. | ||
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| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. | |
|
|
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|
|
|
|
|
|
| Strong CYP2D6 or CYP3A4 inhibitors | Administer half of usual dose |
| Strong CYP2D6 and CYP3A4inhibitors | Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
| ↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
||
|
|
|
|
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 32% |
| Phenobarbital/primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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||
| Phenytoin
|
NC or 25% increase
a
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
b
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
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| Concomitant Drug Name or Drug Class | Clinical Rationale and Magnitude of Drug Interaction | Clinical Recommendation |
|---|---|---|
| Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure | Consider dose reduction |
| Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure | Consider dose increase |
| Specific Drugs Reported | |||
| also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide |
diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine |
lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone |
propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton |
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|||||
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose Recommendation |
||
| |
Coadministered Drug |
Risperidone |
AUC |
Cmax |
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
|
Re-evaluate dosing. |
| |
20 mg/day |
4 mg/day |
1.6 |
|
Do not exceed 8 mg/day |
| |
40 mg/day |
4 mg/day |
1.8 |
|
|
| Enzyme (CYP3A/ PgP inducers) Inducers |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| |
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| Other Drugs |
|
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|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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| Drug Class: Drug Name | Clinical Comment |
|---|---|
| Alpha 1-adrenoreceptor antagonist: alfuzosin |
Potentially increased alfuzosin concentrations can result in hypotension. |
| Antiarrhythmics: amiodarone, quinidine |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| Antimycobacterial: rifampin |
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents. |
| Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| Herbal Products: St. John's wort (hypericum perforatum) |
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents. |
| HMG-CoA Reductase Inhibitors: lovastatin, simvastatin |
Potential for serious reactions such as risk of myopathy including rhabdomyolysis. |
| Neuroleptic: pimozide |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| PDE5 inhibitor: sildenafil (REVATIO) [for treatment of pulmonary arterial hypertension] |
A safe and effective dose has not been established when used with VIRACEPT. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). |
| Proton Pump Inhibitors | Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance. |
| Sedative/Hypnotics: midazolam, triazolam |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression. |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours | Simultaneous dosing of Vardenafil and Alpha-Blocker | ||||
| Alpha-Blocker | Vardenafil 10 mg Placebo-Subtracted |
Vardenafil 20 mg Placebo-Subtracted |
Vardenafil 10 mg Placebo-Subtracted |
Vardenafil 20 mg Placebo-Subtracted |
|
| Terazosin 10 mg daily |
Standing SBP | -7 (-10, -3) | -11 (-14, -7) | -23 (-31, 16) |
-14 (-33, 11) |
| Supine SBP | -5 (-8, -2) | -7 (-11, -4) | -7 (-25, 19) |
-7 (-31, 22) |
|
| Tamsulosin 0.4 mg daily |
Standing SBP | -4 (-8, -1) | -8 (-11, -4) | -8 (-14, -2) | -8 (-14, -1) |
| Supine SBP | -4 (-8, 0) | -7 (-11, -3) | -5 (-9, -2) | -3 (-7, 0) | |
| NA = Not available/reported | |||
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Concentration Increase |
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| CYP2C9
|
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
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aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
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| CYP1A2
|
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
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montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
|
| CYP3A4
|
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
|
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide
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Avoid atorvastatin |
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| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary | |
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Do not exceed 20 mg atorvastatin daily |
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| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily | |
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| Calcium channel blockers | Nifedipine, nimodipine, nisoldipine, verapamil |
| Other | Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine |
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| I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur: |
||
| Drug | Description of Interaction | |
|---|---|---|
| Tolbutamide; Sulfonylureas | Hypoglycemia potentiated | |
| Methotrexate | Decrease tubular reabsorption; clinical toxicity from methotrexate can result | |
| Oral Anticoagulants | Increased bleeding | |
|
II. Drugs changing salicylate levels by altering renal tubular reabsorption: |
||
| Drug | Description of Interaction | |
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism | |
| Ammonium Sulfate | Increases plasma salicylate level | |
|
III. Drugs with complicated interactions with salicylates: |
||
| Drug | Description of Interaction | |
| Heparin | Salicylate decreases platelet adhesivesness and interferes with hemostasis in heparin-treated patients | |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia | |
| Uricosuric Agents | Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited | |
|
The following alterations of laboratory tests have been reported during salicylate therapy6: |
||
| Laboratory Tests | Effect of Salicylates | |
| Thyroid Function | Decreased PBI; increased T3 uptake | |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2 - 5 g qd) | |
| 5 Hydroxyindole Acetic Acid | False negative with fluorometric test | |
| Acetone, Ketone Bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling | |
| 17-OH Corticosteroids | False reduced values with >4.8 g qd salicylate | |
| Vanilmandelic Acid | False reduced values | |
| Uric Acid | May increase or decrease depending on dose | |
| Prothrombin | Decreased levels; slightly increased prothrombin time | |
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A temporary withdrawal of Omeprazole Delayed-Release Capsules may be considered in some patients receiving high-dose methotrexate. |
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Potential for increased exposure of phenytoin. |
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Increased exposure of diazepam |
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Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
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Potential for increased exposure of digoxin |
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Temporarily stop Omeprazole Delayed-Release Capsules treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
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Temporarily stop Omeprazole Delayed-Release Capsules treatment at least 14 days before assessing to allow gastrin levels to return to baseline |
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An alternative confirmatory method should be considered to verify positive results. |
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There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
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Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with Omeprazole Delayed-Release Capsules. |
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The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice |
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The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase |
|
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If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression. |
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Rifampin, carbamazepine, phenytoin |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
|
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
|
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected. |
|
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome |
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The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
|
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs. |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
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Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. | |
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. | |
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Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Clarithromycin | 500 twice daily, 7 days |
800 three times daily, 7 days | 12 | 1.19 (1.02, 1.39) |
1.47 (1.30, 1.65) |
1.97 (1.58, 2.46) n=11 |
| Efavirenz | 200 once daily, 14 days |
800 three times daily, 14 days | 20 | No significant change | No significant change | -- |
| Ethinyl Estradiol (ORTHO-NOVUM 1/35) |
35 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.02 (0.96, 1.09) |
1.22 (1.15, 1.30) |
1.37 (1.24, 1.51) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 8 days | 11 | 1.34 (1.12, 1.60) |
1.12 (1.03, 1.22) |
1.00 (0.92, 1.08) |
| Methadone |
20-60 once daily in the morning, 8 days |
800 three times daily, 8 days | 12 | 0.93 (0.84, 1.03) |
0.96 (0.86, 1.06) |
1.06 (0.94, 1.19) |
| Norethindrone (ORTHO-NOVUM 1/35) |
1 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.05 (0.95, 1.16) |
1.26 (1.20, 1.31) |
1.44 (1.32, 1.57) |
| Rifabutin 150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone |
150 once daily in the morning, 10 days 300 once daily in the morning, 10 days |
800 three times daily, 10 days 800 three times daily, 10 days |
14 10 |
1.29 (1.05, 1.59) 2.34 (1.64, 3.35) |
1.54 (1.33, 1.79) 2.73 (1.99, 3.77) |
1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9 |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 4 |
1.61 (1.13, 2.29) |
1.72 (1.20, 2.48) |
1.62 (0.93, 2.85) |
| 200 twice daily, 14 days |
800 twice daily, 14 days |
9, 5 |
1.19 (0.85, 1.66) |
1.96 (1.39, 2.76) |
4.71 (2.66, 8.33) n=9, 4 |
|
| Saquinavir | ||||||
| Hard gel formulation | 600 single dose | 800 three times daily, 2 days | 6 | 4.7 (2.7, 8.1) |
6.0 (4.0, 9.1) |
2.9 (1.7, 4.7) |
| Soft gel formulation | 800 single dose | 800 three times daily, 2 days | 6 | 6.5 (4.7, 9.1) |
7.2 (4.3, 11.9) |
5.5 (2.2, 14.1) |
| Soft gel formulation | 1200 single dose | 800 three times daily, 2 days | 6 | 4.0 (2.7, 5.9) |
4.6 (3.2, 6.7) |
5.5 (3.7, 8.3) |
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| Stavudine |
40 twice daily, 7 days |
800 three times daily, 7 days | 13 | 0.86 (0.73, 1.03) |
1.21 (1.09, 1.33) |
Not Done |
| Theophylline | 250 single dose (on Days 1 and 7) | 800 three times daily, 6 days (Days 2 to 7) | 12, 4 |
0.88 (0.76, 1.03) |
1.14 (1.04, 1.24) |
1.13 (0.86, 1.49) n=7, 3 |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Trimethoprim | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.18 (1.05, 1.32) |
1.18 (1.05, 1.33) |
1.18 (1.00, 1.39) |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Sulfamethoxazole | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.01 (0.95, 1.08) |
1.05 (1.01, 1.09) |
1.05 (0.97, 1.14) |
| Vardenafil | 10 single dose | 800 three times daily | 18 | See text below for discussion of interaction. | ||
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days | 12 | 0.89 (0.73, 1.09) |
1.17 (1.07, 1.29) |
1.51 (0.71, 3.20) n=4 |
| Zidovudine/ Lamivudine |
||||||
| Zidovudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
1.23 (0.74, 2.03) |
1.39 (1.02, 1.89) |
1.08 (0.77, 1.50) n=5, 5 |
| Zidovudine/ Lamivudine |
||||||
| Lamivudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
0.73 (0.52, 1.02) |
0.91 (0.66, 1.26) |
0.88 (0.59, 1.33) |
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(e.g,. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone
|
Do not exceed 10 mg simvastatin daily
|
| Amiodarone, amlodipine, ranolazine
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Do not exceed 20 mg simvastatin daily
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| Lomitapide
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For patients with HoFH, do not exceed 20 mg simvastatin daily*
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| Grapefruit juice
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Avoid grapefruit juice
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| Interacting Drug | Interaction |
|---|---|
| Multivalent cation – containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| Concomitant Drug Class: Drug Name |
Effect on Concentration of Darunavir or Concomitant Drug | Clinical Comment |
|---|---|---|
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| didanosine | ↔ darunavir ↔ didanosine |
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food). |
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| indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.) |
↑ darunavir ↑ indinavir |
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established. |
| lopinavir/ritonavir | ↓ darunavir ↔ lopinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir. |
| saquinavir | ↓ darunavir ↔ saquinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir. |
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| maraviroc | ↑ maraviroc | Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily. |
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|
bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone |
↑ antiarrhythmics | Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir. |
| digoxin | ↑ digoxin | The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect. |
|
warfarin |
↓ warfarin ↔ darunavir |
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir. |
|
carbamazepine |
↔ darunavir ↑ carbamazepine |
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response. |
|
phenobarbital, phenytoin |
↔ darunavir ↓ phenytoin ↓ phenobarbital |
Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir. |
|
trazodone, desipramine |
↑ trazodone ↑ desipramine |
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered. |
|
clarithromycin |
↔ darunavir ↑ clarithromycin |
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered:
|
|
ketoconazole, itraconazole, voriconazole |
↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied) |
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir. |
| Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg. | ||
| Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole. | ||
|
colchicine |
↑ colchicine |
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir. |
|
rifabutin |
↑ darunavir ↑ rifabutin ↑ 25- |
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary. |
| The reference regimen for rifabutin was 300 mg once daily | ||
|
metoprolol, timolol |
↑ beta-blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
|
parenterally administered midazolam |
↑ midazolam | Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED. |
|
felodipine, nifedipine, nicardipine |
↑ calcium channel blockers | Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended. |
|
dexamethasone |
↓ darunavir | Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. |
|
fluticasone |
↑ fluticasone | Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use. |
|
bosentan |
↑ bosentan |
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
NS3-4A protease inhibitors: boceprevir telaprevir |
↓ darunavir ↓ boceprevir ↓ telaprevir |
|
|
pravastatin, atorvastatin, rosuvastatin |
↑ pravastatin ↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day. |
|
cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir. |
|
salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
|
methadone, buprenorphine, buprenorphine/naloxone |
↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite) |
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered. |
|
risperidone, thioridazine |
↑ neuroleptics | A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
|
ethinyl estradiol, norethindrone |
↓ ethinyl estradiol ↓ norethindrone |
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended. |
|
sildenafil, vardenafil, tadalafil |
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) |
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events. |
|
sertraline, paroxetine |
↔ darunavir ↓ sertraline ↓ paroxetine |
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response. |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole tablets with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole tablets alone |
Withconcomitant use of aripiprazole tablets with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole tablets dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole tablets and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole tablets alone |
Withconcomitant use of aripiprazole tablets with a strong CYP3A4 inducer, consider increasing the aripiprazole tablets dosage |
| AntihypertensiveDrugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor bloodpressure and adjust dose accordingly |
| Benzodiazepines(e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
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| Dopamine/Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone
Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. | ||
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| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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twice daily |
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Do not exceed 8 mg/day |
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Do not exceed 8 mg/day |
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twice daily |
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Do not exceed twice the patient’s usual dose |
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four times daily |
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| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Oral hypoglycemics Coumarin-type anticoagulants Phenytoin Cyclosporine Rifampin Theophylline Voriconazole Tofacitinib Oral Contraceptives Hydrochlorothiazide Amitriptyline, nortriptyline Azithromycin Calcium Channel Blockers Cyclophosphamide |
Quinidine Halofantrine Losartan Non-steroidal anti-inflammatory drugs Saquinavir Vinca Alkaloids Zidovudine Terfenadine Cisapride Astemizole Rifabutin Tacrolimus Short-acting benzodiazepines |
Triazolam Pimozide Alfentanil Amphotericin B Carbamazepine Celecoxib Fentanyl HMG-CoA reductase inhibitors Methadone Prednisone Sirolimus Vitamin A |
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| Phenytoin |
NC or 25% increasea
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48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP450 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,
posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin
|
| Verapamil, diltiazem, dronedarone
|
Do not exceed 10 mg simvastatin daily
|
| Amiodarone, amlodipine, ranolazine
|
Do not exceed 20 mg simvastatin daily
|
| Lomitapide
|
For patients with HoFH, do not exceed
20 mg simvastatin daily |
| Grapefruit juice
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Avoid grapefruit juice
|
| * The interaction between immediate-release nevirapine tablets and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine tablets are expected to also apply to nevirapine extended-release tablets. | ||
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| Atazanavir/Ritonavir* |
↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* Fosamprenavir/Ritonavir* |
↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* |
↓ Indinavir |
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* |
↓Lopinavir |
Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* |
↓ Nelfinavir M8 Metabolite ↓ Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir |
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated |
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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| Efavirenz* |
↓ Efavirenz |
The appropriate doses of these combinations with respect to safety and efficacy have not been established. |
| Delavirdine Etravirine Rilpivirine |
|
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
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| Boceprevir |
Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. |
Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy. |
| Telaprevir |
Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. |
Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events. |
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|
Methadone* |
↓ Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Clarithromycin* |
↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Rifabutin* |
↑ Rifabutin |
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin* |
↓ Nevirapine |
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* |
↑ Nevirapine |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Ketoconazole* |
↓ Ketoconazole |
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Itraconazole |
↓ Itraconazole |
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine extended-release tablets, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception When oral contraceptives are used for hormonal regulation during nevirapine extended-release tablets therapy, the therapeutic effect of the hormonal therapy should be monitored. |
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| Calcium channel blockers | Nifedipine, nimodipine, nisoldipine, verapamil |
| Other | Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine |
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Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. |
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Because these effects may be additive, coadministration of TREXIMET and ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) within 24 hours of each other is contraindicated. |
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MAO-A inhibitors increase systemic exposure of orally administered sumatriptan by 7-fold. |
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The use of TREXIMET in patients receiving MAO-A inhibitors is contraindicated. |
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5-HT1 agonist drugs can cause vasospastic effects. |
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Because these effects may be additive, coadministration of TREXIMET and other 5 HT1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. |
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Monitor patients with concomitant use of TREXIMET with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone |
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Concomitant use of TREXIMET and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding |
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Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors |
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Discontinue TREXIMET if serotonin syndrome is suspected. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of TREXIMET with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects |
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The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of TREXIMET and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
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During concomitant use of TREXIMET and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant administration of some NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of TREXIMET and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of NSAIDs and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of TREXIMET and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy |
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The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. |
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Concomitant use of NSAIDs and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of TREXIMET and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. The clinical significance of this is unknown. |
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Reduce the frequency of administration of Treximet when given concurrently with probenecid. |
| DRUG | DISCRIPTION OF INTERACTION |
|---|---|
| Sulfonylureas | Hypoglycemia potentiated |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. |
| Oral Anticoagulants | Increased bleeding |
| Specific Drugs Reported | |||
| also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
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| acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide
|
diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine
|
lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone
|
propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton
|
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Raltegravir | Clinical Comment |
|---|---|---|
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| atazanavir | ↑ | Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| atazanavir/ritonavir | ↑ | Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| efavirenz | ↓ | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| etravirine | ↓ | Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| tipranavir/ritonavir | ↓ | Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended. |
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| omeprazole | ↑ | Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| rifampin | ↓ | Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. |
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Quinidine Dofetilide Amiodarone Sotalol Procainamide |
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Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
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Colchicine (in patients with normal renal and hepatic function) |
Use With Caution |
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Etravirine |
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Didanosine |
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The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated. |
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Diltiazem |
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Dihydroergotamine |
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Simvastatin |
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Pravastatin |
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Pioglitazone Repaglinide Rosiglitazone |
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Tadalafil Vardenafil |
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Triazolam |
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In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
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Nitrazepam Lorazepam |
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Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
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Phenytoin Valproate |
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Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to |
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Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. |
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Nevirapine Rifampicin Rifapentine |
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| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| *Change relative to reference
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| Coadministered Drug
|
Dosing Schedule
|
Effect on Active Moiety
(Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose
Recommendation |
||
| Coadministered Drug
|
Risperidone
|
AUC
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Cmax
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| Enzyme (CYP2D6) inhibitors
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| Fluoxetine
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20 mg/day
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2 or 3 mg twice daily
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1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
-
|
Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day
|
4 mg/day
|
1.6
|
-
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||
| 40 mg/day
|
4 mg/day
|
1.8
|
-
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||
| Enzyme (CYP3A/ PgP inducers) Inducers
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| Carbamazepine
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573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) inhibitors
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|
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| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not needed
|
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not needed
|
| Erythromycin
|
500 mg four times daily
|
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not needed
|
| Other Drugs
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|
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|
|
|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not Needed
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|
|
Multivalent cation-containing products including antacids, metal cation or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. |
|
Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
|
Antidiabetic agent |
Carefully monitor blood glucose |
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There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists. |
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Closely monitor patients with concurrent use of BUTRANS and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BUTRANS, and warn patients to use benzodiazepines concurrently with BUTRANS only as directed by their physician. |
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Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing
of these drugs for use in patients for whom alternative treatment
options are inadequate. Limit dosages and durations to the minimum
required. Follow patients closely for signs of respiratory depression
and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of buprenorphine
and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine,
resulting in increased or prolonged opioid effects, particularly when
an inhibitor is added after a stable dose of BUTRANS is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease |
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If concomitant use is necessary,
consider dosage reduction of BUTRANS until stable drug effects are
achieved. Monitor patients for respiratory depression and sedation
at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the BUTRANS dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
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The concomitant use of buprenorphine
and CYP3A4 inducers can decrease the plasma concentration of buprenorphine After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase |
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If concomitant use is necessary,
consider increasing the BUTRANS dosage until stable drug effects are
achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider BUTRANS dosage reduction and monitor for signs of respiratory depression. |
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Rifampin, carbamazepine, phenytoin |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue BUTRANS if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids
may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory
depression, coma) |
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The use of BUTRANS is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of BUTRANS and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine |
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Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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|
Monitor patients receiving muscle relaxants and BUTRANS for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of BUTRANS and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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|
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of opioid analgesics, including buprenorphine, and anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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|
Monitor patients for signs of urinary retention or reduced gastric motility when BUTRANS is used concomitantly with anticholinergic drugs. |
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Hepatitis C protease inhibitor (boceprevir) |
|
| Concomitant Drug Class: Drug Name | Effect | Clinical Comment |
|---|---|---|
|
|
||
| Protease inhibitor: atazanavir |
↓atazanavir ↑ tenofovir |
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. |
| Protease inhibitor: fosamprenavir calcium |
↓ amprenavir | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. |
| Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. | ||
| Protease inhibitor: indinavir |
↓ indinavir | The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Protease inhibitor: lopinavir/ritonavir |
↓ lopinavir ↑ tenofovir |
Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions. |
| Protease inhibitor: ritonavir |
↑ ritonavir ↑ efavirenz |
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. |
| Protease inhibitor: saquinavir |
↓ saquinavir | Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
| CCR5 co-receptor antagonist: maraviroc |
↓ maraviroc | Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA. |
| NRTI: didanosine |
↑ didanosine | Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information. |
| NNRTI: Other NNRTIs |
↑ or ↓ efavirenz and/or NNRTI | Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs. |
| Integrase strand transfer inhibitor: raltegravir |
↓ raltegravir | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
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|
||
| Protease inhibitor: boceprevir |
↓ boceprevir | Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided. |
| Protease inhibitor: simeprevir |
↓ simeprevir ↔ efavirenz |
Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir. |
| NS5A inhibitor/NS5B polymerase inhibitor : ledipasvir/sofosbuvir |
↑ tenofovir | Patients receiving ATRIPLA and HARVONI™ (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF. |
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|
||
| Anticoagulant: warfarin |
↑ or ↓ warfarin | Plasma concentrations and effects potentially increased or decreased by efavirenz. |
| Anticonvulsants: carbamazepine |
↓ carbamazepine ↓ efavirenz |
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. |
| phenytoin phenobarbital |
↓ anticonvulsant ↓ efavirenz |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants: bupropion |
↓ buproprion | The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| sertraline | ↓ sertraline | Increases in sertraline dose should be guided by clinical response. |
| Antifungals: itraconazole |
↓ itraconazole ↓ hydroxy-itraconazole |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| ketoconazole | ↓ ketoconazole | Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. |
| posaconazole | ↓ posaconazole | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective: clarithromycin |
↓ clarithromycin ↑ 14-OH metabolite |
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA. |
| Antimycobacterial: rifabutin |
↓ rifabutin | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| rifampin | ↓ efavirenz | If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended. |
| Antimalarials: artemether/lumefantrine |
↓ artemether ↓ dihydroartemisinin ↓ lumefantrine |
Artemether/lumefantrine should be used cautiously with ATRIPLA because decreased artemether, dihydroartemisinin (active metabolite of artemether), and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of artemether/lumefantrine. |
| Calcium channel blockers: diltiazem |
↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. |
| Others (e.g., felodipine, nicardipine, nifedipine, verapamil) | ↓ calcium channel blocker | No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin |
↓ atorvastatin ↓ pravastatin ↓ simvastatin |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: | ||
| Oral: ethinyl estradiol/norgestimate |
↓ active metabolites of norgestimate | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant: etonogestrel |
↓ etonogestrel | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immuno-suppressant | Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. |
| Narcotic analgesic: methadone |
↓ methadone | Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
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Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
|
|
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Injection and/or the muscle relaxant as necessary. |
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The concomitant administration of morphine sulfate and cimetidine has been reported to precipitate apnea, confusion and muscle twitching in an isolated report. |
|
|
Monitor patients for increased respiratory and CNS depression when receiving cimetidine concomitantly with Morphine Sulfate Injection. |
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|
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
|
|
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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|
|
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
|
|
Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Injection is used concomitantly with anticholinergic drugs. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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|
|
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Antineoplastic agents usually in combination | Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate |
| Antiviral agents | Fosamprenavir, nelfinavir, ritonavir |
| Antiepileptic drugs | Carbamazepine, vigabatrin |
| Other |
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| Antiepileptic drugs | Phenobarbital, valproate sodium, valproic acid |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓lamotrigine ↓levonorgestrel |
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels |
| Lopinavir/ ritonavir |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| blood dyscrasias — | diarrhea | hyperthyroidism |
| see |
elevated temperature | poor nutritional state |
| cancer | hepatic disorders | steatorrhea |
| collagen vascular disease | infectious hepatitis | vitamin K deficiency |
| congestive heart failure | jaundice |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
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Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. |
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Dose reductions and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs. |
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Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones |
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Dose increases and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs. |
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Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. |
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Dose adjustment and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs. |
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beta-blockers, clonidine, guanethidine, and reserpine |
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Increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs. |
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
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| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
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|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
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| Enzyme (CYP2D6) Inhibitors |
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| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
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20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
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40 mg/day |
4 mg/day |
1.8 |
- |
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| Enzyme (CYP3A/ PgP inducers) |
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| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
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| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
| |
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| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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Monitor patients with concomitant use of naproxen with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone |
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Concomitant use of naproxen and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see |
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• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
|
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• During concomitant use of naproxen and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of naproxen with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see |
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| *Change relative to reference |
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Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Recommendation |
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Inhibitors |
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daily |
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PgP inducers) |
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Do not exceed twice the patient’s usual dose |
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Inhibitors |
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needed |
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needed |
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daily |
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needed |
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needed |
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Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
| |
|
| |
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg). |
| |
Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Celecoxib is not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
| |
During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
| |
During concomitant use of celecoxib and digoxin, monitor serum digoxin levels. |
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| |
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
| |
During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics. |
| |
During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity. |
| |
During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
| |
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. |
| |
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Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
| |
During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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| |
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
| |
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ |
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Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding. |
| |
Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine |
Decreased lamotrigine concentrations approximately 50%. |
|
|
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
| Carbamazepine and epoxide |
↓ lamotrigine |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
|
|
? Carbamazepine epoxide |
May increase Carbamazepine epoxide levels. |
| Lopinavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine |
Increased lamotrigine concentrations slightly more than 2-fold. |
|
|
? valproate |
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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Hepatitis C protease inhibitor (boceprevir) |
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| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin | Monitor phenytoin level ( |
| Methotrexate | Monitor for methotrexate toxicity ( |
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine | Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets ( |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Raltegravir | Clinical Comment |
|---|---|---|
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| aluminum and/or magnesium-containing antacids | ↓ | Coadministration or staggered administration of aluminum and/or magnesium hydroxide-containing antacids and ISENTRESS is not recommended. |
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| rifampin | ↓ | The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age |
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The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated. |
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| AED Coadministered | Dose of AED
(mg/day) |
Oxcarbazepine Tablets Dose
(mg/day) |
Influence of Oxcarbazepine Tablets on AED Concentration
(Mean Change, 90% Confidence Interval) |
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc
|
40% decrease
[CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase
[CI: 2% increase, 24% increase] |
25% decrease
[CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800
>1200-2400 |
nc
[CI: 12% increase, 60% increase] |
30% decrease
[CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc
|
18% decrease
[CI: 13% decrease, 40% decrease] |
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| Dopamine / Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
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| Aminoglutethimide
Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone
Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4, and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. |
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| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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Norepinephrine Dopamine |
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| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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(Cmax and AUCτ) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP450 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Amlodipine Aspirin Atorvastatin Calcitriol Clopidogrel Digoxin Diltiazem Doxercalciferol Enalapril Fluvastatin Glimepiride Levofloxacin Losartan Metoprolol Pravastatin Propranolol Sitagliptin Warfarin |
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| Doxycycline | Take at least 1 hour before Auryxia |
| Ciprofloxacin | Take at least 2 hours before or after Auryxia |
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Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
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Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [
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The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib capsules have no effect on methotrexate pharmacokinetics. |
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During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [
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Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see
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Drug Name |
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| valsartan*
losartan* candesartan* |
↑ angiotensin receptor blockers | Decrease the dose of the angiotensin receptor blockers and monitor patients for signs and symptoms of hypotension and/or worsening renal function. If such events occur, consider further dose reduction of the angiotensin receptor blocker or switching to an alternative to the angiotensin receptor blocker. |
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| amiodarone*, bepridil*, disopyramide*, flecainide*, lidocaine (systemic)*, mexiletine*, propafenone*, quinidine* |
↑ antiarrhythmics | Contraindicated antiarrhythmics Therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with VIEKIRA XR. |
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| metformin | ↔ metformin | Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Concomitant metformin use in patients with renal insufficiency or hepatic impairment is not recommended. Refer to the prescribing information of metformin for further guidance. |
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| ketoconazole | ↑ ketoconazole | When VIEKIRA XR is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day. |
| voriconazole* | ↓ voriconazole | Co-administration of VIEKIRA XR with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole. |
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| quetiapine* | ↑ quetiapine | Contraindicated antipsychotics Quetiapine:
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| amlodipine nifedipine* diltiazem* verapamil* |
↑ calcium channel blockers | Decrease the dose of the calcium channel blocker. The dose of amlodipine should be decreased by at least 50%. Clinical monitoring of patients is recommended for edema and/or signs and symptoms of hypotension. If such events occur, consider further dose reduction of the calcium channel blocker or switching to an alternative to the calcium channel blocker. |
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| fluticasone* | ↑ fluticasone | Concomitant use of VIEKIRA XR with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use. |
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| furosemide | ↑ furosemide (Cmax) | Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response. |
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| atazanavir/ritonavir once daily |
↑ paritaprevir | When coadministered with VIEKIRA XR, atazanavir 300 mg (without ritonavir) should only be given in the morning. |
| darunavir/ritonavir | ↓ darunavir (Ctrough) | Treatment naïve patients or treatment experienced patients with no darunavir associated substitutions: Darunavir 800 mg once daily (without ritonavir) can be co-administered with VIEKIRA XR. Treatment experienced patients with at least one darunavir resistance associated substitution or with no baseline resistance information: Co-administration of darunavir/ritonavir 600/100 mg twice daily with VIEKIRA XR is not recommended. |
| lopinavir/ritonavir | ↑ paritaprevir | Co-administration of VIEKIRA XR with lopinavir/ritonavir is not recommended. |
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| rilpivirine | ↑ rilpivirine | Contraindicated non-nucleoside reverse transcriptase inhibitors Rilpivirine: Co-administration of VIEKIRA XR with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine. |
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| pravastatin rosuvastatin |
↑ pravastatin ↑ rosuvastatin |
Contraindicated HMG CoA Reductase Inhibitors Rosuvastatin: Dose of rosuvastatin should not exceed 10 mg per day. Pravastatin: Dose of pravastatin should not exceed 40 mg per day. |
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| cyclosporine | ↑ cyclosporine | For contraindicated immunosuppressants When initiating therapy with VIEKIRA XR, reduce cyclosporine dose to 1/5th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of VIEKIRA XR therapy, the appropriate time to resume pre-VIEKIRA XR dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended. |
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| salmeterol* | ↑ salmeterol | Concurrent administration of VIEKIRA XR and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
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| carisoprodol | ↓ carisoprodol ↔ mepobramate (metabolite of carisoprodol) |
Increase dose if clinically indicated. |
| cyclobenzaprine | ↓cyclobenzaprine ↓norcyclobenzaprine (metabolite of cyclobenzaprine) |
Increase dose if clinically indicated. |
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| acetaminophen/hydrocodone | ↑ hydrocodone ↔ acetaminophen |
Reduce the dose of hydrocodone by 50% and monitor patients for respiratory depression and sedation at frequent intervals. Upon completion of VIEKIRA XR therapy, adjust the hydrocodone dose and monitor for signs of opioid withdrawal. |
| buprenorphine/naloxone | ↑ buprenorphine ↑ norbuprenorphine (metabolite of buprenorphine) |
Patients should be closely monitored for sedation and cognitive effects. |
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| omeprazole | ↓ omeprazole | Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole. |
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| alprazolam | ↑ alprazolam | Contraindicated Sedatives/Hypnotics Alprazolam: Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response. |
| diazepam | ↓ diazepam ↓ nordiazepam (metabolite of diazepam) |
Increase dose if clinically indicated. |
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The direction of the arrow indicates the direction of the change in exposures (Cmax and AUC) (↑ = *not studied. |
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| Clinical Impact: | The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology • There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole. |
| Intervention: | Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs. |
| |
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| Clinical Impact: | Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
| Intervention: | Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. |
| |
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| Clinical Impact: | Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions |
| Intervention: | A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. |
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| Clinical Impact: | Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [ There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. |
| Intervention: | Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions |
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| Clinical Impact: | Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology |
| Intervention: | Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. |
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| Clinical Impact: | Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology |
| Intervention: | Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. |
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| Clinical Impact: | Potential for increased exposure of phenytoin. |
| Intervention: | Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. |
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| Clinical Impact: | Increased exposure of diazepam [see Clinical Pharmacology |
| Intervention: | Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
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| Clinical Impact: | Potential for increased exposure of digoxin [see Clinical Pharmacology |
| Intervention: | Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. |
| |
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| Clinical Impact: | Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
| Intervention: | Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology |
| |
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| Clinical Impact: | Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. |
| Intervention: | See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin. |
| |
|
| Clinical Impact: | Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. |
| Intervention: | Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
| |
|
| Clinical Impact: | Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions |
| Intervention: | Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
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| Clinical Impact: | Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
| Intervention: | Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology |
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| Clinical Impact: | There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
| Intervention: | An alternative confirmatory method should be considered to verify positive results. |
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| Clinical Impact: | There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
| Intervention: | Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole. |
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| Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
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|
Iodide (including iodine-containing radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases theophylline clearance at allopurinol doses ≥600 mg/day. | 25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects. | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium. to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic seizure threshold. | May lower theophylline |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
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| Antihypertensive Drugs |
Because of its α1-adrenergic antagonism with potential for inducing hypotension, SAPHRIS may enhance the effects of certain antihypertensive agents |
Monitor blood pressure and adjust dosage of antihypertensive drug accordingly. |
| Strong CYP1A2 Inhibitors (e.g., Fluvoxamine) | SAPHRIS is metabolized by CYP1A2. Marginal increase of asenapine exposure was observed when SAPHRIS is used with fluvoxamine at 25 mg administered twice daily |
Dosage reduction for SAPHRIS based on clinical response may be necessary. |
| CYP2D6 substrates and inhibitors (e.g., paroxetine) | SAPHRIS may enhance the inhibitory effects of paroxetine on its own metabolism. Concomitant use of paroxetine with SAPHRIS increased the paroxetine exposure by 2-fold as compared to use paroxetine alone |
Reduce paroxetine dose by half when paroxetine is used in combination with SAPHRIS. |
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| Known CYP2D6 Poor Metabolizers |
Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors |
Administer a quarter of usual dose |
| Strong CYP2D6 or CYP3A4 inhibitors |
Administer half of usual dose |
| Strong CYP2D6 and CYP3A4 inhibitors |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers |
Double usual dose over 1 to 2 weeks |
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Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. |
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|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. |
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|
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). |
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
|
|
|
| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
|
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|
|||
| Dopamine/Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone
Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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|
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||
| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. | ||
|
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|
|
|||
| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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Significant decrease in plasma
naldemedine concentrations, which may reduce efficacy |
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Avoid use of SYMPROIC with strong CYP3A inducers. |
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Potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal. |
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Avoid use of SYMPROIC with another opioid antagonist. |
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Increase in plasma naldemedine
concentrations |
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Monitor for potential naldemedine-related
adverse reactions |
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Increase in plasma naldemedine
concentrations |
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Monitor for potential naldemedine-related
adverse reactions |
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| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level (
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| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (
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| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (
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| Phenytoin | Monitor phenytoin level (
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| Methotrexate | Monitor for methotrexate toxicity (
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| Cyclosporine | May increase serum creatinine. Monitor serum creatinine (
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| Multivalent cation-containing products including antacids, metal cations, or didanosine | Decreased Ciprofloxacin absorption. Take 2 hours before or 6 hours after Ciprofloxacin (
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| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Strong CYP2D6 or CYP3A4 inhibitors | Administer half of usual dose |
| Strong CYP2D6 and CYP3A4inhibitors | Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
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| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 50 mg (95% CI) |
|---|---|
| Supine | 9.08 (5.48, 12.68) |
| Standing |
11.62 (7.34, 15.90) |
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See prescribing information for voriconazole. |
| Drugs That are Affected by Ciprofloxacin | ||
|---|---|---|
| Drug(s) | Recommendation | Comments |
| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ |
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [ |
| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [ |
| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine | Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant (for example, warfarin). |
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [ |
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil | Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity [ |
| Duloxetine | Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity. |
| Caffeine/Xanthine Derivatives | Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
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| Probenecid | Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) | Potentiation of ciprofloxacin toxicity may occur. |
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Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (
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Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. |
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Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis |
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Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. |
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Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). |
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Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
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Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
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Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
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|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
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Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
|
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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| valsartan*, losartan*, candesartan* |
↑ angiotensin receptor blockers | Decrease the dose of the angiotensin receptor blockers and monitor patients for signs and symptoms of hypotension and/or worsening renal function. If such events occur, consider further dose reduction of the angiotensin receptor blocker or switching to an alternative to the angiotensin receptor blocker. |
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| digoxin | ↑ digoxin | For contraindicated antiarrhythmics Decrease digoxin dose by 30-50%. Appropriate monitoring of serum digoxin levels is recommended. |
| amiodarone*, bepridil*, disopyramide*, flecainide*, lidocaine (systemic)*, mexiletine*, propafenone*, quinidine* |
↑ antiarrhythmics | Therapeutic monitoring (if available) is recommended for antiarrhythmics when co-administered with TECHNIVIE. |
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| metformin | ↔ metformin | Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Concomitant metformin use in patients with renal insufficiency or hepatic impairment is not recommended. Refer to the prescribing information of metformin for further guidance. |
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| ketoconazole | ↑ ketoconazole | When TECHNIVIE is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day. |
| voriconazole* | ↓ voriconazole | Co-administration of TECHNIVIE with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole. |
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| quetiapine* | ↑ quetiapine | For contraindicated antipsychotics
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| amlodipine, nifedipine*, diltiazem*, verapamil* |
↑ calcium channel blockers | Decrease the dose of the calcium channel blocker. The dose of amlodipine should be decreased by at least 50%. Clinical monitoring of patients is recommended for edema and/or signs and symptoms of hypotension. If such events occur, consider further dose reduction of the calcium channel blocker or switching to an alternative to the calcium channel blocker. |
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| fluticasone* | ↑ fluticasone | Concomitant use of TECHNIVIE with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use. |
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| furosemide | ↑ furosemide (Cmax) | Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response. |
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| atazanavir or atazanavir/ritonavir | ↑ paritaprevir | Co-administration of TECHNIVIE with atazanavir or atazanavir/ritonavir is not recommended. |
| darunavir/ritonavir | ↓ darunavir (Ctrough) | Treatment naïve patients or treatment experienced patients with no darunavir-associated mutations: Darunavir 800 mg once daily (without ritonavir) can be co-administered with TECHNIVIE. |
| lopinavir/ritonavir | ↑ paritaprevir | Co-administration of TECHNIVIE with lopinavir/ritonavir is not recommended. |
| rilpivirine | ↑ rilpivirine | For contraindicated non-nucleoside reverse transcriptase inhibitors Co-administration of TECHNIVIE with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine. |
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| pravastatin | ↑ pravastatin | For contraindicated HMG CoA Reductase Inhibitors When TECHNIVIE is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day. |
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| cyclosporine | ↑ cyclosporine | For contraindicated immunosuppressants When initiating therapy with TECHNIVIE, reduce cyclosporine dose to 1/5th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of TECHNIVIE therapy, the appropriate time to resume pre-TECHNIVIE dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended. |
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| salmeterol* | ↑ salmeterol | Concurrent administration of TECHNIVIE and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
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| carisoprodol | ↓ carisoprodol ↔ mepobramate (metabolite of carisoprodol) |
Increase dose if clinically indicated. |
| cyclobenzaprine | ↓cyclobenzaprine ↓norcyclobenzaprine (metabolite of cyclobenzaprine) |
Increase dose if clinically indicated. |
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| buprenorphine/naloxone | ↑ buprenorphine ↑ norbuprenorphine (metabolite of buprenorphine) |
Patients should be closely monitored for sedation and cognitive effects. |
| Hydrocodone/ acetaminophen |
↑ hydrocodone ↔ acetaminophen |
Reduce the dose of hydrocodone by 50% and monitor patients for respiratory depression and sedation at frequent intervals. Upon completion of TECHNIVIE therapy, adjust the hydrocodone dose and monitor for signs of opioid withdrawal. |
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| omeprazole | ↓ omeprazole | Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole. |
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| alprazolam | ↑ alprazolam | For contraindicated Sedatives/Hypnotics Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response. |
| diazepam | ↓ diazepam ↓ nordiazepam (metabolite of diazepam) |
Increase dose if clinically indicated. |
| *Not studied. The direction of the arrow indicates the direction of the change in exposures (Cmax and AUC) (↑ = |
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Nevirapine or Concomitant Drug |
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| Atazanavir/Ritonavir |
↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir |
↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir |
↓ Amprenavir ↑ Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir |
↓ Indinavir |
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir |
↓Lopinavir |
Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir |
↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir |
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated |
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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| Efavirenz |
↓ Efavirenz |
The appropriate doses of these combinations with respect to safety and efficacy have not been established. |
| Delavirdine Etravirine Rilpivirine |
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
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| Boceprevir |
Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. |
Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy. |
| Telaprevir |
Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. |
Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events. |
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| Methadone |
↓ Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
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| Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Clarithromycin |
↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
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| Rifabutin |
↑ Rifabutin |
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin |
↓ Nevirapine |
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
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| Fluconazole |
↑Nevirapine |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Ketoconazole |
↓ Ketoconazole |
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Itraconazole |
↓ Itraconazole |
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increase. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. |
Appropriate doses for this combinations have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. |
Appropriate doses for this combinations have not been established. |
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| Ethinyl estradiol and Norethindrone |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| NA – Not available/reported | |||
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Concentration Increase |
Increase |
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diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole, |
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cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine |
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were studied but reported no significant changes on digoxin exposure. |
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| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
|---|---|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
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|
|
|
|
|
|
|
| Phenytoin
|
NCor25%increase
a
|
48%decrease
|
| Carbamazepine(CBZ)
|
NC
|
40%decrease
|
| CBZepoxide
b
|
NC
|
NE
|
| Valproic acid
|
11%decrease
|
14%decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NCatTPM dosesupto400 mg/day
|
13%decrease
|
|
|
|
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|
|
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|
| Drug/Drug Class (Mechanism of Interaction by the Drug) |
Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg Q12h) |
Recommendations for Voriconazole Dosage Adjustment/Comments |
| Rifampin (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (CYP450 Induction) |
Significantly Reduced | When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See |
| High-dose Ritonavir (400mg Q12h) (CYP450 Induction) |
Significantly Reduced |
|
| Low-dose Ritonavir (100mg Q12h) (CYP450 Induction) |
Reduced | Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction |
|
| Phenytoin (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hrs or from 200 mg to 400 mg orally every 12 hrs (100 mg to 200 mg orally every 12 hrs in patients weighing less than 40 kg) |
| St. John's Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) |
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
| Other NNRTIs (CYP3A4 Inhibition or CYP450 Induction) |
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) | Frequent monitoring for adverse events and toxicity related to voriconazole |
|
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Careful assessment of voriconazole effectiveness |
| edema | hypothyroidism |
| hereditary coumarin resistance | nephrotic syndrome |
| hyperlipemia |
|
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
|
| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓= Decreased (induces lamotrigine gluronidation). | ||
| ↑= Increased (inhibits lamotrigine glucuronidation). | ||
| ?= Conflicting data. | ||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
|
|
(mg/day) |
(mg/day) |
Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400-2000 | 900 | nc 1 | 40% decrease
[CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase
[CI: 2% increase, 24% increase] |
25% decrease
[CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800
>1200-2400 |
nc
1,2
up to 40% increase 3 [CI: 12% increase, 60% increase] |
30% decrease
[CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc 1 | 18% decrease
[CI: 13% decrease, 40% decrease] |
|
|
|
|
Inflammatory Drugs |
Agents |
|
|
| ciprofloxacin |
melphalan | amphotericin B |
azapropazon |
cimetidine |
tacrolimus |
fibric acid derivatives (e.g., bezafibrate, fenofibrate) |
| |
|
|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
|
|
|
|
|
|
| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
|
|
|
|
|
|
| Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| |
||
| |
||
| |
||
| |
||
| |
||
| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
|
|
|
| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level (
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| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (
|
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (
|
| Phenytoin | Monitor phenytoin level (
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| Methotrexate | Monitor for methotrexate toxicity (
|
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine (
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets (
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Avoid atorvastatin
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| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary | |
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Do not exceed 20 mg atorvastatin daily
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| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily | |
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| Phenytoin
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NCor25%increase
a
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48%decrease
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| Carbamazepine(CBZ)
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NC
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40%decrease
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| CBZepoxide
b
|
NC
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NE
|
| Valproic acid
|
11%decrease
|
14%decrease
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| Phenobarbital
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NC
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NE
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| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NCatTPM dosesupto400 mg/day
|
13%decrease
|
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
|
NC or 25% increase
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
|
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
|
|
|
| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin | Monitor phenytoin level ( |
| Methotrexate | Monitor for methotrexate toxicity ( |
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine | Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( |
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Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
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In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
| albuterol, systemic and inhaled | felodipinefinasteride | nizatidinenorfloxacin |
| amoxicillin | hydrocortisone | ofloxacin |
| ampicillin, with or without sulbactam | isoflurane isoniazid | omeprazole prednisone, prednisolone |
| atenolol | isradipine | ranitidine |
| azithromycin | influenze vaccine | rifabutin |
| caffeine, dietary ingestion | ketoconazo lelomefloxacin | Roxithromycin sorbitol (purgative doses do onot inhibit theophylline absorption) |
| cefaclor | mebendazole | |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | medroxyprogesteronemethylprednisolone | sucralfate |
| diltiazem | metronidazole | terbutaline, systemic |
| dirithromycin | metoprolol | terfenadine |
| enflurane | nadolol | tetracycline |
| famotidine | nifedipine | tocainide |
| Coadministered drug (Postulated effect on CYP450/UGT) |
Dose schedules | Effect on asenapine pharmacokinetics | Recommendation | ||
|---|---|---|---|---|---|
| Coadministered drug | Asenapine | Cmax | AUC0-∞ | ||
| Fluvoxamine (CYP1A2 inhibitor) |
25 mg twice daily for 8 days | 5-mg Single Dose | +13% | +29% | Coadminister with caution |
| Paroxetine (CYP2D6 inhibitor) |
20 mg once daily for 9 days | 5-mg Single Dose | –13% | –9% | No SAPHRIS dose adjustment required |
| Imipramine (CYP1A2/2C19/3A4 inhibitor) |
75-mg Single Dose | 5-mg Single Dose | +17% | +10% | No SAPHRIS dose adjustment required |
| Cimetidine (CYP3A4/2D6/1A2 inhibitor) |
800 mg twice daily for 8 days | 5-mg Single Dose | –13% | +1% | No SAPHRIS dose adjustment required |
| Carbamazepine (CYP3A4 inducer) |
400 mg twice daily for 15 days |
5-mg Single Dose | –16% | –16% | No SAPHRIS dose adjustment required |
| Valproate (UGT1A4 inhibitor) |
500 mg twice daily for 9 days | 5-mg Single Dose | 2% | –1% | No SAPHRIS dose adjustment required |
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| Clinical Impact: | Decreased exposure of omeprazole when used concomitantly with strong inducers [see |
| Intervention: | St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see |
| |
|
| Clinical Impact: | Increased exposure of omeprazole [see |
| Intervention: | Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole. |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases theophylline clearance at allopurinol doses ≥600 mg/day. | 25% increase |
| Aminoglutethimide | Increase theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant while, theophylline blocks adenosine receptors | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects of nausea, nervousness, and insomnia. | Increased frequency of nausea, nervousness, and insomnia |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine | Similar to cimetidine |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine. | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize nondepolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction | 100% increase Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease |
| Tacrine | Similar to cimetidine, also increase renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
|
Function |
angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin. |
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Analog |
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Agents |
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and calcium channel blockers |
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| DRUG | DESCRIPTION OF INTERACTION |
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| Pyrazinamide | Inhibits pyrazinamide induced hyperuricemia. |
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. |
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| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – Antagonist: maraviroc |
↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
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| Antiarrhythmics e.g.: amiodarone, bepridil, lidocaine (systemic), quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulants: warfarin, rivaroxaban |
↑ rivaroxaban | Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding. |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Anticonvulsants: lamotrigine, valproate |
↓ lamotrigine ↓ or ↔ valproate |
Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroids (systemic): e.g. budesonide, dexamethasone, prednisone |
↓ lopinavir ↑ glucocorticoids |
Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. |
| Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HCV-Protease Inhibitor: boceprevir |
↓ lopinavir ↓ boceprevir ↓ ritonavir |
It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures |
| HCV-Protease Inhibitor: telaprevir |
↓ telaprevir ↔ lopinavir |
It is not recommended to co-administer KALETRA and telaprevir. Concomitant administration of KALETRA and telaprevir reduced steady-state telaprevir exposure, while the steady-state lopinavir exposure was not affected |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA |
| Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled or Intranasal Steroids e.g.: fluticasone, budesonide |
↑ glucocorticoids | Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide. |
| Long-acting beta-adrenoceptor Agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesics: methadone,* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil |
↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil |
Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
| * |
||
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|
| Theophylline |
Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents |
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin |
Monitor phenytoin level ( |
| Methotrexate |
Monitor for methotrexate toxicity ( |
| Cyclosporine |
May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( |
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|
| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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( |
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| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
|
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(Cmax and AUC |
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Efavirenz (300 mg q24h)** (CYP450 Induction) |
Slight Decrease in AUCτ |
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Reduced |
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
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indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
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| Coadministered Drug
|
Dosing Schedule
|
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)
|
|
Risperidone Dose Recommendation
|
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|
Coadministered Drug
|
Risperidone
|
AUC
|
C
m
a
x
|
|
| Enzyme (CYP2D6) Inhibitors
|
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|
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|
|
| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice daily
|
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day
|
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
-
|
Re-evaluate dosing.
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|
20 mg/day
|
4 mg/day
|
1.6
|
-
|
Do not exceed 8 mg/day
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|
40 mg/day
|
4 mg/day
|
1.8
|
-
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| Enzyme (CYP3A/ PgP inducers)
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| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards. Do not exceed twice the patient’s usual dose
|
| Enzyme (CYP3A) Inhibitors
|
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| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not needed
|
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not needed
|
| Erythromycin
|
500 mg four times daily
|
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not needed
|
| Other Drugs
|
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|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not needed
|
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|
| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin | Monitor phenytoin level ( |
| Methotrexate | Monitor for methotrexate toxicity ( |
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine | Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( |
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The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of naproxen and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
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During concomitant use of naproxen and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of naproxen and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of naproxen and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of naproxen and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy |
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The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. |
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Concomitant use of naproxen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of naproxen and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
| * For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. | |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
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| Coadministered Drug
|
Dosing Schedule
|
|
Effect on Active
Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose
Recommendation |
|
|
Coadministered Drug
|
Risperidone
|
AUC
|
C
m
a
x
|
|
| Enzyme (CYP2D6)
Inhibitors |
|
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|
|
| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice
daily |
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day
|
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
-
|
Re-evaluate dosing.
|
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|
20 mg/day
|
4 mg/day
|
1.6
|
-
|
Do not exceed 8 mg/day
|
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|
40 mg/day
|
4 mg/day
|
1.8
|
-
|
|
| Enzyme (CYP3A/
PgP inducers) |
|
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|
|
|
| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards.
Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)
Inhibitors |
|
|
|
|
|
| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not
needed |
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not
needed |
| Erythromycin
|
500 mg four times
daily |
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not
needed |
| Other Drugs
|
|
|
|
|
|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not
needed |
| NA – Not available/reported | |||
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Concentration Increase |
Increase |
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diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole, |
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|
cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine |
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were studied but reported no significant changes on digoxin exposure. |
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| Antacids, sucralfate, multivitamins, and other products containing multivalent cations |
Moxifloxacin absorption is decreased. Administer moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin |
Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: |
Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Drug or Drug Class | Effect |
|---|---|
|
|
|
| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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● Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. ● Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of diclofenac sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see WARNINGS AND PRECAUTIONS ( |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of NSAID alone [see WARNINGS AND PRECAUTIONS ( |
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Concomitant use of diclofenac sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS ( |
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● NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). ● In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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● During concomitant use of diclofenac sodium and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained ● During concomitant use of diclofenac sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see WARNINGS AND PRECAUTIONS( |
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Clinical studies, as well as post-marketing observations, showed that NSAIDS reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of diclofenac sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see WARNINGS AND PRECAUTIONS ( |
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The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life digoxin. |
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During concomitant use of diclofenac sodium and digoxin, monitor serum digoxin levels. |
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NSAIDS have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of diclofenac sodium and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of diclofenac sodium and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of diclofenac sodium and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of diclofenac sodium and cyclosporine, monitor patients for signs or worsening renal function. |
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Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see WARNINGS AND PRECAUTIONS ( |
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The concomitant use of diclofenac with other NSAIDs or salicyclates is not recommended. Do not use combination therapy with diclofenac sodium and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations |
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Concomitant use of diclofenac sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of diclofenac sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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| Digoxin Serum Concentration Increase | Digoxin AUC Increase |
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| Amiodarone | 70% | NA | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring. |
| Captopril | 58% | 39% | |
| Nitrendipine | 57% | 15% | |
| Propafenone | 35-85% | NA | |
| Quinidine | 100% | NA | |
| Ranolazine | 87% | 88% | |
| Ritonavir | NA | 86% | |
| Verapamil | 50-75% | NA | |
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| Carvedilol | 16% | 14% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring. |
| Diltiazem | 20% | NA | |
| Nifedipine | 45% | NA | |
| Rabeprazole | 29% | 19% | |
| Telmisartan | 20% | NA | |
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| Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline | Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. | ||
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Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary. | ||
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| Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. | No additional actions are required. | ||
|
a ENVARSUS XR dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures b High dose or double strength grapefruit juice is a c Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting |
||||
| Drug/Substance Class or Name | Drug Interaction Effect | Recommendations | ||
| Grapefruit or grapefruit juiceb | May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) |
Avoid grapefruit or grapefruit juice | ||
| Alcohol | May modify the rate of tacrolimus release | Avoid alcoholic beverages | ||
| Strong CYP3A Inducersc such as: Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s Wort |
May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection |
Increase ENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations |
||
| Strong CYP3A Inhibitorsc, such as: Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone |
May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) |
Reduce ENVARSUS XR dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations |
||
| Mild or Moderate CYP3A Inhibitors, such as: antibiotics (e.g., erythromycin), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole, azole antifungals (e.g., clotrimazole, fluconazole) |
May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) |
Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed |
||
| Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide |
May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) |
Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed |
||
| Mild or Moderate CYP3A Inducers, such as: Methylprednisolone, prednisone |
May decrease tacrolimus concentrations | Monitor tacrolimus whole blood trough concentrations and adjust ENVARSUS XR dose if needed |
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| Warfarin |
Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: |
Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
| Antidiabetic agents | Carefully monitor blood glucose. ( |
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|---|---|
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including antacids, metal cations or didanosine |
formulation is taken within 2 hours of this product. |
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INR, watch for bleeding |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
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Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| voriconazole | quinupristin/ dalfopristin |
colchicine | ||
| danazol | ||||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
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| AED Co-administered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increasea | 48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxideb | NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
|
a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated |
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NE = Not Evaluated. |
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| Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin |
Not Recommended Use With Caution |
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
|
| Oral Anticoagulants: Warfarin |
Use With Caution |
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| Antiepileptics: Carbamazepine |
Use With Caution |
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| Antifungals: Itraconazole Fluconazole |
Use With Caution No Dose Adjustment |
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| Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function) |
Contraindicated Use With Caution |
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| Antipsychotics: Pimozide Quetiapine |
Contraindicated |
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| Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity) |
Use With Caution |
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| Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine |
Use With Caution No Dose Adjustment |
Maraviroc Zidovudine: |
|
| Calcium Channel Blockers: Verapamil Amlodipine Diltiazem Nifedipine |
Use With Caution |
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| Ergot Alkaloids: Ergotamine Dihydroergotamine |
Contraindicated |
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| Gastroprokinetic Agents: Cisapride |
Contraindicated |
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| HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin |
Contraindicated Use With Caution No Dose Adjustment |
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| Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin |
Use With Caution |
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| Immunosuppressants: Cyclosporine Tacrolimus |
Use With Caution |
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| Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil |
Use With Caution |
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| Proton Pump Inhibitors: Omeprazole |
No Dose Adjustment |
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| Xanthine Derivatives: Theophylline |
Use With Caution |
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| Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam |
Use With Caution No Dose Adjustment |
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
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| Cytochrome P450 Inducers: Rifabutin |
Use With Caution |
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| Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution |
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. |
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| Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate |
Use With Caution |
There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. |
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Drugs that Affect Clarithromycin |
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Recommendation |
Comments |
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| Antifungals: Itraconazole |
Use With Caution |
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| Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function) |
Use With Caution No Dose Adjustment |
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. |
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| Proton Pump Inhibitors: Omeprazole |
Use With Caution |
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| Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine |
Use With Caution |
Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above). |
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Hepatitis C protease inhibitor (boceprevir) |
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If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. |
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| Co-administered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) | Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6)Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | Re-evaluate dosing. Do not exceed 8 mg/day | |
| Enzyme (CYP3A/PgP inducers)Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| a Should be administered at least 4 hours prior to WELCHOL | |
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b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an |
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| d Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs. | |
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| Drugs with a known interaction with colesevelam: Decrease in exposure of coadministered drug |
cyclosporinec, glimepiridea, glipizidea, glyburidea, levothyroxinea, olmesartan medoxomila, and oral contraceptives containing ethinyl estradiol and norethindronea |
| Drugs with a known interaction with colesevelam: Increase in exposure of coadministered drug |
metformin extended release (ER)d |
| Drug(s) with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL |
phenytoina, warfarinb |
| Drugs that do not interact with colesevelam based on |
aspirin, atenolol, cephalexin, ciprofloxacin, digoxin, enalapril, fenofibrate, lovastatin, metformin, metoprolol, phenytoina, pioglitazone, rosiglitazone, quinidine, repaglinide, sitagliptin, valproic acid, verapamil, warfarinb |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , )
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Avoid atorvastatin
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| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
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Do not exceed 20 mg atorvastatin daily
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| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)
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Do not exceed 40 mg atorvastatin daily |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, fibrates |
Avoid VYTORIN |
| Cyclosporine, danazol | Do not exceed 10/10 mg VYTORIN daily |
| Amiodarone, verapamil | Do not exceed 10/20 mg VYTORIN daily |
| Diltiazem | Do not exceed 10/40 mg VYTORIN daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| * For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. | |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily* |
| Grapefruit juice |
Avoid grapefruit juice |
| CYP450 Inhibitors | Recommended CERDELGA Dosage for PMs |
|---|---|
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e.g., ketoconazole |
Contraindicated |
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e.g., fluconazole |
Not recommended |
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e.g., ranitidine |
Not recommended |
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine
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Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (
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| Warfarin
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Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
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| Antidiabetic agents
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Carefully monitor blood glucose (
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| Strong CYP2D6 or CYP3A4 inhibitors | Administer half of usual dose |
| Strong CYP2D6 and CYP3A4inhibitors | Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
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Decreased exposure of omeprazole when used concomitantly with strong inducers |
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St. John’s Wort, rifampin: Avoid concomitant use with omeprazole Ritonavir-containing products: see prescribing information for specific drugs. |
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Increased exposure of omeprazole |
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Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole. |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Drug Class: Drug Name |
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| Antiarrhythmics: amiodarone, quinidine |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| Antimycobacterial: rifampin |
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents. |
| Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| Herbal Products: St. John's wort (hypericum perforatum) |
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents. |
| HMG-CoA Reductase Inhibitors: lovastatin, simvastatin |
Potential for serious reactions such as risk of myopathy including rhabdomyolysis. |
| Neuroleptic: pimozide |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| Proton Pump Inhibitors | Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance. |
| Sedative/Hypnotics: midazolam, triazolam |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression. |
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
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| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Known CYP2D6 Poor Metabolizers | Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP2D6 or CYP3A4 inhibitors | Administer half of usual dose |
| Strong CYP2D6 and CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | |
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | |
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. |
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| Allopurinol |
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25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. |
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| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increase theophylline clearance. | 20% increase |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20 to 40% decrease |
| Sulfinpyrazone | Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% increase |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33 to 100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
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| Clinical Impact: | Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. | |
| Intervention: |
Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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| Clinical Impact: |
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
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| Intervention: |
Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
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| Clinical Impact: | NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. | |
| Intervention: |
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [
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| Clinical Impact: |
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [
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| Intervention: |
Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [
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| Clinical Impact: | The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. | |
| Intervention: | During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. | |
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| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. | |
| Intervention: | During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. | |
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| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). | |
| Intervention: | During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity. | |
| Intervention: | During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. | |
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| Clinical Impact: |
Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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| Intervention: | The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. | |
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||
| Clinical Impact: | Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). | |
| Intervention: | During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. | |
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||
| Clinical Impact: | When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. | |
| Intervention: | During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. | |
| AED Coadministered | Dose of AED
(mg/day) |
Oxcarbazepine Tablets Dose
(mg/day) |
Influence of Oxcarbazepine Tablets on AED Concentration
(Mean Change, 90% Confidence Interval) |
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc
|
40% decrease
[CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase
[CI: 2% increase, 24% increase] |
25% decrease
[CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800
>1200-2400 |
nc
[CI: 12% increase, 60% increase] |
30% decrease
[CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc
|
18% decrease
[CI: 13% decrease, 40% decrease] |
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initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. |
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| Drug | Description of Interaction |
|---|---|
| Tolbutamide; Sulfonylureas |
Hypoglycemia potentiated |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result |
| Oral Anticoagulants | Increased bleeding |
| Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. | |
|
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|
| Calcium Carbonate Ferrous Sulfate |
Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents. |
| Orlistat | Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function. |
| Bile Acid Sequestrants - Colesevelam - Cholestyramine - Colestipol Ion Exchange Resins - Kayexalate - Sevelamer |
Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels. |
| Other drugs: Proton Pump Inhibitors Sucralfate Antacids - Aluminum & Magnesium Hydroxides - Simethicone |
Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately. |
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|---|---|---|---|
| NA – Not available/reported | |||
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anti-platelet therapy |
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(3,4-dihydro-cilostazol) |
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| Multivalent cation-containing products including antacids,
metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (
|
| Warfarin
|
Effect may be enhanced. Monitor prothrombin
time, INR, watch for bleeding ( |
| Antidiabetic agents
|
Carefully monitor blood glucose (
|
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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|
|
The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
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|
|
Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
|
|
Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. |
|
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|
|
Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted |
|
|
A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. |
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|
|
Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. |
|
|
Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy |
|
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|
|
Increased exposure of citalopram leading to an increased risk of QT prolongation |
|
|
Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. |
|
|
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|
|
Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) |
|
|
Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. |
|
|
|
|
|
Potential for increased exposure of phenytoin. |
|
|
Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. |
|
|
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|
|
Increased exposure of diazepam |
|
|
Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
|
|
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|
|
Potential for increased exposure of digoxin |
|
|
Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. |
|
|
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|
|
Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
|
|
Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF See the prescribing information for other drugs dependent on gastric pH for absorption. |
|
|
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|
|
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. |
| Amoxicillin also has drug interactions. | |
|
|
See See |
|
|
|
|
|
Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. |
|
|
Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
|
|
|
|
|
Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors |
|
|
Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
|
|
|
|
|
Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
|
|
Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline |
|
|
|
|
|
There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
|
|
An alternative confirmatory method should be considered to verify positive results. |
|
|
|
|
|
There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
|
|
Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole. |
|
|
|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone. |
|
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|
products including antacids, metal cations or didanosine |
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|||||
| Coadministered Drug
|
Dosing Schedule
|
Effect on Active
Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose
Recommendation |
||
|
|
Coadministered Drug
|
Risperidone
|
AUC
|
Cmax
|
|
| Enzyme (CYP2D6)
Inhibitors |
|
|
|
|
|
| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice
daily |
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day
|
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
|
Re-evaluate dosing.
|
|
|
20 mg/day
|
4 mg/day
|
1.6
|
|
Do not exceed 8 mg/day
|
|
|
40 mg/day
|
4 mg/day
|
1.8
|
|
|
| Enzyme (CYP3A/ PgP inducers) Inducers
|
|
|
|
|
|
| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards.
Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)
Inhibitors |
|
|
|
|
|
| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not
needed |
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not
needed |
| Erythromycin
|
500 mg four times
daily |
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not
needed |
|
|
|
|
|
|
|
| Other Drugs
|
|
|
|
|
|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not
needed |
|
|
|
|
|
|
|
Glucocorticoids Octreotide |
|
|
|
|
|
|
|
|
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
|
|
|
|
|
Iodide (including iodine-containing Radiographic contrast agents) |
|
|
|
|
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
|
|
|
|
|
|
|
|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
|
|
|
|
|
|
|
|
Hydantoins Phenobarbital Rifampin |
|
|
|
|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
|
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
|
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
|
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
|
|
|
|
|
- Interferon-α - Interleukin-2 |
|
|
- Somatrem - Somatropin |
|
|
|
|
|
- (e.g., Theophylline) |
|
|
|
|
|
|
|
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
|
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone
Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. | ||
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| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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| Drug | Type of Interaction | Effect† |
|---|---|---|
| * † interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed. |
||
| Adenosine | Theophylline blocks adenosine
receptors. |
Higher doses of adenosine may be required to achieve
desired effect. |
| Alcohol | A single large dose of alcohol (3
mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. |
30% increase |
| Allopurinol | Decreases theophylline clearance
at allopurinol doses ≥600 mg/day. |
25% increase |
| Aminoglutethimide | Increases theophylline clearance
by induction of microsomal enzyme activity. |
25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance
by inhibiting cytochrome P450 1A2. |
70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS
concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. |
Larger diazepam doses may be required to produce
desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance
by inhibiting hydroxylation and demethylation. |
50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects. | Increased frequency of nausea, nervousness, and
insomnia. |
| Erythromycin | Erythromycin metabolite
decreases theophylline clearance by inhibiting cytochrome P450 3A3. |
35% increase. Erythromycin steady-state serum
concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral
contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown. |
30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine |
| Halothane | Halothane sensitizes the
myocardium to catecholamines, theophylline increases release of endogenous catecholamines. |
Increased risk of ventricular arrhythmias. |
| Interferon, human
recombinant alpha-A |
Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic. | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal
lithium clearance. |
Lithium dose required to achieve a therapeutic serum
concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX
may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize
non-depolarizing neuromuscular blocking effects, possibly due to phosphodiesterase inhibition. |
Larger dose of pancuronium may be required to
achieve neuromuscular blockade |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline
clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. |
Serum theophylline decrease about 40%. |
| Propafenone | Decreases theophylline clearance
and pharmacologic interaction. |
40% increase. Beta2 blocking effect may decrease
efficacy of theophylline |
| Propranolol | Similar to cimetidine and
pharmacologic interaction. |
100% increase. Beta2 blocking effect may decrease
efficacy of theophylline |
| Rifampin | Increases theophylline clearance
by increasing cytochrome P450 1A2 and 3A3 activity. |
20-40% decrease |
| St. John's Wort
(Hypericum Perforatum) |
Decrease in theophylline plasma
concentrations. |
Higher doses of theophylline may be required to
achieve desired effect. Stopping St. John's Wort may result in theophylline toxicity. |
| Sulfinpyrazone | Increases theophylline clearance
by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. |
20% decrease |
| Tacrine | Similar to cimetidine, also
increases renal clearance of theophylline. |
90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
| |
|
| Known CYP2D6 Poor Metabolizers | Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP2D6 |
Administer half of usual dose |
| Strong CYP2D6 |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
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|
(Peak plasma concentration) |
(Extent of systemic exposure) |
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel
|
↓ lamotrigine
|
Decreased lamotrigine levels approximately 50%.
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↓ levonorgestrel
|
Decrease in levonorgestrel component by 19%.
|
| Carbamazepine (CBZ) and CBZ epoxide
|
↓ lamotrigine
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
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? CBZ epoxide
|
May increase CBZ epoxide levels
|
| Phenobarbital/Primidone
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 40%.
|
| Phenytoin (PHT)
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 40%
|
| Rifampin
|
↓ lamotrigine
|
Decreased lamotrigine AUC approximately 40%
|
| Valproate
|
↑ lamotrigine
|
Increased lamotrigine concentrations slightly more than 2-fold.
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? valproate
|
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
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| ↑ increase, ↓ decrease, ↔ no change, ↕ unable to predict | ||
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Drug name |
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HIV-1 Antiviral Agents |
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|
Enfuvirtide |
↑ Tipranavir |
At steady state, tipranavir trough concentrations were approximately 45% higher in patients co-administered enfuvirtide in the Phase 3 trials. The mechanism for this increase is not known. Dose adjustments are not recommended. |
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Etravirine |
↓ Etravirine |
APTIVUS/ritonavir when coadministered with etravirine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine. Etravirine and APTIVUS/ritonavir should not be coadministered. |
| Rilpivirine | The use of rilpivirine co-administered with APTIVUS/ritonavir has not been studied. | Concomitant use of rilpivirine with Aptivus/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Rilpivirine is not expected to affect the plasma concentrations of Aptivus/ritonavir. |
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|
Abacavir |
↓ Abacavir AUC by approximately 40% |
Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time. |
| Didanosine (EC) | ↓ Didanosine | Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from APTIVUS/ritonavir dosing by at least 2 hours. |
| Zidovudine | ↓ Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered. | Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time. |
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| Fosamprenavir Lopinavir Saquinavir |
↓ Amprenavir ↓ Lopinavir ↓ Saquinavir |
Combining a protease inhibitor with APTIVUS/ritonavir is not recommended. |
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| Atazanavir | ↓ Atazanavir ↑ Tipranavir |
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| Raltegravir | ↓ Raltegravir | APTIVUS/ritonavir reduces plasma concentrations of raltegravir. Since comparable efficacy was observed for this combination in phase 3 studies, dose adjustment is not recommended. |
|
Agents for Opportunistic Infections |
||
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| Fluconazole Itraconazole Ketoconazole Voriconazole |
↑ Tipranavir, ↔ Fluconazole | Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Fluconazole doses >200 mg/day are not recommended. |
| ↑ Itraconazole (not studied) | ||
| ↑ Ketoconazole (not studied) | Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses (>200 mg/day) are not recommended. | |
| ↕ Voriconazole (not studied) | ||
| Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction. | ||
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| Clarithromycin | ↑ Tipranavir, ↑ Clarithromycin, ↓ 14-hydroxy-clarithromycin metabolite |
No dose adjustment of APTIVUS or clarithromycin for
patients with normal renal function is necessary. |
For patients with renal impairment the following dosage adjustments
should be considered:
|
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| Rifabutin | Tipranavir not changed, ↑ Rifabutin ↑ Desacetyl-rifabutin |
Single dose study. Dosage reductions of rifabutin by 75% are recommended (e.g., 150 mg every other day). Increased monitoring for adverse events in patients receiving the combination is warranted. Further dosage reduction may be necessary. |
| Other Agents Commonly Used |
||
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| Carbamazepine Phenobarbital Phenytoin |
↓ Tipranavir | Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentration in patients taking these agents concomitantly. |
| Valproic Acid | ↓ Valproic Acid | Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentration in patients taking APTIVUS concomitantly. |
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| Trazodone | ↑ Trazodone | Concomitant use of trazodone and APTIVUS/ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP 3A4 inhibitor such as APTIVUS/ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Desipramine | Combination with APTIVUS/ritonavir not studied ↑ Desipramine |
Dosage reduction and concentration monitoring of desipramine is recommended. |
| Selective Serotonin-Reuptake Inhibitors: | Combination with APTIVUS/ritonavir not studied | Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of APTIVUS/ritonavir therapy. |
| Fluoxetine Paroxetine Sertraline |
↑ Fluoxetine ↑ Paroxetine ↑ Sertraline |
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| Boceprevir | Co-administration of APTIVUS and boceprevir has not been studied. | With concomitant use, changes in exposure were observed both for
boceprevir and certain protease inhibitors used for the treatment
of HIV-1 infection or either medication. Information is not available
regarding tipranavir or boceprevir exposure with concomitant use.
It is not recommended to co-administer boceprevir with APTIVUS/ritonavir. |
| Telaprevir | Co-administration of APTIVUS and telaprevir has not been studied. | With concomitant use, changes in exposure were observed both for telaprevir and certain protease inhibitors used for the treatment of HIV-1 infection or telaprevir. Information is not available regarding tipranavir or telaprevir exposure with concomitant use. It is not recommended to co-administer telaprevir with APTIVUS/ritonavir. |
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| Colchicine | ↑ Colchicine | In patients with renal or hepatic impairment, coadministration
of colchicine in patients on APTIVUS/ritonavir is contraindicated. In combination with APTIVUS/ritonavir, the following dosage adjustments are recommended in patients with normal renal and hepatic function:
|
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| Quetiapine | ↑ Quetiapine |
Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
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| Parenterally administered midazolam | ↑ Midazolam | Midazolam is extensively metabolized by CYP 3A4.
Increases in the concentration of midazolam are expected to be significantly
higher with oral than parenteral administration. Therefore, APTIVUS
should not be given with orally administered midazolam [ |
| Buprenorphine/naloxone | ↔ Buprenorphine ↓ Tipranavir |
APTIVUS/ritonavir did not result in changes in the clinical efficacy of buprenorphine/naloxone. Compared to historical controls tipranavir Cmin was decreased approximately 40% with this combination. Dose adjustments cannot be recommended. |
|
Diltiazem Felodipine Nicardipine Nisoldipine Verapamil |
Combination with APTIVUS/ritonavir
not studied. Cannot predict effect of TPV/ritonavir on calcium channel
blockers that are dual substrates of CYP3A and P-gp due to conflicting
effect of TPV/ritonavir on CYP3A and P-gp. ↕ Diltiazem ↑ Felodipine (CYP3A substrate but not P-gp substrate) ↕ Nicardipine ↕ Nisoldipine (CYP3A substrate but not clear whether it is a P-gp substrate) ↕ Verapamil |
Caution is warranted and clinical monitoring of patients is recommended. |
| Disulfiram/Metronidazole | Combination with TPV/ritonavir not studied | APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole). |
|
Bosentan |
↑ Bosentan |
In patients who have been receiving APTIVUS/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of APTIVUS/ritonavir. After at least 10 days following the initiation of APTIVUS/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
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| Atorvastatin Rosuvastatin |
↑ Atorvastatin ↓ Hydroxy-atorvastatin metabolites ↑ Rosuvastatin |
Avoid co-administration with atorvastatin. |
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| Combination with APTIVUS/ritonavir not studied | Careful glucose monitoring is warranted. | |
| Glimepiride Glipizide Glyburide Pioglitazone |
↔ Glimepiride (CYP 2C9) ↔ Glipizide (CYP 2C9) ↔ Glyburide (CYP 2C9) ↕ Pioglitazone (CYP 2C8 and CYP 3A4) |
|
| Repaglinide | ↕ Repaglinide (CYP 2C8 and CYP 3A4) | |
| Tolbutamide | ↔ Tolbutamide (CYP 2C9) The effect of TPV/ritonavir on CYP 2C8 substrate is not known. |
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| Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on immunosuppressants due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp. | Increased frequency of monitoring of plasma levels of immunosuppressant drugs is recommended. | |
| Cyclosporine Sirolimus Tacrolimus |
↕ Cyclosporine ↕ Sirolimus ↕ Tacrolimus |
|
|
Salmeterol |
↑ Salmeterol |
Concurrent administration of APTIVUS/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
|
|
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| Fluticasone | ↑ Fluticasone | Concomitant use of fluticasone propionate and APTIVUS/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone propionate and APTIVUS/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. |
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| Combinations with APTIVUS/ritonavir not studied | Dosage increase and long-term use of meperidine are not recommended due to increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures). | |
| Meperidine | ↓ Meperidine, ↑ Normeperidine | |
| Methadone | ↓ Methadone ↓ S-Methadone, ↓ R-Methadone |
Dosage of methadone may need to be increased when co-administered with APTIVUS and 200 mg of ritonavir. |
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| Ethinyl estradiol | ↓ Ethinyl estradiol concentrations by 50% | Alternative methods of nonhormonal contraception should be used when estrogen based oral contraceptives are co-administered with APTIVUS and 200 mg of ritonavir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Women using estrogens may have an increased risk of non-serious rash. |
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|
Omeprazole |
↓ Omeprazole, ↔ Tipranavir |
Dosage of omeprazole may need to be increased when co-administered with APTIVUS and ritonavir. |
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|
Sildenafil Tadalafil Vardenafil |
Only the combination of tadalafil with APTIVUS/ritonavir has been studied (at doses used for treatment of erectile dysfunction). | Co-administration with APTIVUS/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. |
|
↑ Sildenafil (not studied) ↑ Tadalafil with first dose APTIVUS/ritonavir ↔ Tadalafil at APTIVUS/ritonavir steady-state ↑ Vardenafil (not studied) |
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Concomitant use of PDE-5 inhibitors with APTIVUS/ritonavir should be used with caution and in no case should the starting dose of:
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||
| Warfarin | ↔ S-Warfarin | Frequent INR (international normalized ratio) monitoring upon initiation of APTIVUS/ritonavir therapy. |
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Concentration of Lamotrigine or Concomitant Drug |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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| Known CYP2D6 Poor Metabolizers | Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP2D6 |
Administer half of usual dose |
| Strong CYP2D6 |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
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| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
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| Known CYP2D6 Poor Metabolizers | Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP2D6 |
Administer half of usual dose |
| Strong CYP2D6 |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
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|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
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|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
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|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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|
|
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
|
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
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|
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
|
|
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [
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|
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
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Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
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During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
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Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
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During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome.
After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression |
|
|
If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome.
If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation. |
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Quinidine, fluoxetine, paroxetine and bupropion
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The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved.
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease |
|
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If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
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The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase |
|
|
If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended. |
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Rifampin, carbamazepine, phenytoin
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected.
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
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MAOI interactions with opioids may manifest as serotonin syndrome
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Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
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phenelzine, tranylcypromine, linezolid
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May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms.
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Avoid concomitant use.
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butorphanol, nalbuphine, pentazocine, buprenorphine
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Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary.
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
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Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets are used concomitantly with anticholinergic drugs.
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Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
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Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed.
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Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
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Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.
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See prescribing information for voriconazole. |
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| CYP2C9
|
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
|
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
|
| CYP1A2
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acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
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montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
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| CYP3A4
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alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
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armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
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Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [
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During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
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Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
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During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
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Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
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During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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| Concomitant Drug Name or Drug Class |
Clinical Rationale and Magnitude of Drug Interaction | Clinical Recommendation |
| Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure |
Consider dose reduction |
| Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure |
Consider dose increase |
| Specific Drugs Reported | |||
|---|---|---|---|
| also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
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| alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone |
cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate |
6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone |
propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage |
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Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
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Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [
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The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib capsules have no effect on methotrexate pharmacokinetics. |
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During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [
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Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see
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| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio
|
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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| HIV-1 Protease Inhibitor:
fosamprenavir/ritonavir |
↓ amprenavir
↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor:
indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with indinavir. |
| HIV-1 Protease Inhibitor:
nelfinavir* |
↑ nelfinavir
↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA once daily in combination with nelfinavir is not recommended
|
| HIV-1 Protease Inhibitor:
ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor:
saquinavir |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor:
tipranavir* |
↓ lopinavir | Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended. |
| HIV CCR5 – Antagonist:
maraviroc* |
↑ maraviroc | When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc. |
| Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*, nevirapine* |
↓ lopinavir | Increase the dose of KALETRA tablets to 500/125 mg when KALETRA tablet is co-administered with efavirenz or nevirapine. KALETRA once daily in combination with efavirenz or nevirapine is not recommended
|
| Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor:
didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor:
tenofovir disoproxil fumarate* |
↑ tenofovir | Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitors:
abacavir zidovudine |
↓ abacavir
↓ zidovudine |
The clinical significance of this potential interaction is unknown. |
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| Antiarrhythmics e.g.
amiodarone, bepridil, lidocaine (systemic), quinidine |
↑ antiarrhythmics | For contraindicated antiarrhythmics,
Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents:
vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulants:
warfarin, rivaroxaban |
↑↓ warfarin
↑ rivaroxaban |
Concentrations of warfarin may be affected. Initial frequent monitoring of the INR during KALETRA and warfarin co-administration is recommended.
Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban may lead to increased risk of bleeding. |
| Anticonvulsants:
carbamazepine, phenobarbital, phenytoin |
↓ lopinavir
↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Anticonvulsants:
lamotrigine, valproate |
↓ lamotrigine
↓ or ↔ valproate |
A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments. |
| Antidepressant:
bupropion |
↓ bupropion
↓ active metabolite, hydroxybupropion |
Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant:
trazodone |
↑ trazodone | Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered. |
| Anti-infective:
clarithromycin |
↑ clarithromycin | For patients with renal impairment, adjust clarithromycin dose as follows:
|
| Antifungals:
ketoconazole*, itraconazole, voriconazole isavuconazonium sulfate* |
↑ ketoconazole
↑ itraconazole ↓ voriconazole ↑ isavuconazonium |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
The coadministration of voriconazole and KALETRA should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Isavuconazonium and Kaletra should be coadministered with caution. Alternative antifungal therapies should be considered in these patients. |
| Anti-gout:
colchicine |
↑ colchicine | Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial:
bedaquiline |
↑ bedaquiline | For contraindicated antimycobacterials,
Bedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk. |
| Antimycobacterial:
rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antiparasitic:
atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Antipsychotics: quetiapine | ↑ quetiapine |
Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
| Sedative/hypnotics:
parenterally administered midazolam |
↑ midazolam | For contraindicated sedative/hypnotics,
If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered. |
| Contraceptive:
ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroids (systemic): e.g.
budesonide, dexamethasone, prednisone |
↓ lopinavir
↑ glucocorticoids |
Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. |
| Dihydropyridine Calcium Channel Blockers: e.g.
felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Clinical monitoring of patients is recommended and a dose reduction of the dihydropyridine calcium channel blocker may be considered. |
| Disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists:
bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| Hepatitis C direct acting antivirals:
boceprevir* simeprevir ombitasvir/parataprevir/ ritonavir and dasabuvir* |
↓ lopinavir
↓ boceprevir ↓ ritonavir ↑simeprevir ↑ ombitsavir ↑ parataprevir ↑ ritonavir ↔ dasabuvir |
For contraindicated hepatitis C direct acting antivirals,
It is not recommended to co-administer KALETRA and boceprevir, simeprevir, or ombitasvir/parataprevir/ritonavir and dasabuvir. |
| HMG-CoA Reductase Inhibitors:
atorvastatin rosuvastatin |
↑ atorvastatin
↑ rosuvastatin |
For contraindicated HMG-CoA reductase inhibitors,
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. |
| Immunosuppressants: e.g.
cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled or Intranasal Steroids e.g.:
fluticasone, budesonide |
↑ glucocorticoids | Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide. |
| Long-acting beta-adrenoceptor Agonist:
salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesics:
methadone,* fentanyl |
↓ methadone
↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA.
Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors:
avanafil, sildenafil, tadalafil, vardenafil |
↑ avanafil
↑ sildenafil ↑ tadalafil ↑ vardenafil |
For contraindicated PDE5 inhibitors,
Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio ®) is contraindicated The following dose adjustments are recommended for use of tadalafil (Adcirca ®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
| *
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Hepatitis C protease inhibitor (boceprevir) |
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| Drug | Effect | |
|---|---|---|
| Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). |
Cardiac pressor response potentiated. May cause acute hypertensive crisis. |
|
| Phenylephrine with tricyclic anti-depressants. |
Pressor response increased. |
|
| Phenylephrine with ergot alkaloids. |
Excessive rise in blood pressure. |
|
| Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. |
Tachycardia or other arrhythmias may occur. | |
| Phenylephrine with prior administration of propranolol or other β-adrenergic blockers. |
Cardiostimulating effects blocked. | |
| Phenylephrine with atropine sulfate. |
Reflex bradycardia blocked; pressor response enhanced. |
|
| Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. |
Pressor response decreased. | |
| Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. |
Synergistic adrenergic response. |
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|
|
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| |
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| |
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| |
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| Alpha Blockers | tamsulosin | |||
| Analgesics | methadone | alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil |
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|
| Antiarrhythmics | disopyramide, dofetilide, dronedarone, quinidine |
digoxin | |
|
| Antibacterials | telithromycin, in subjects with severe renal impairment or severe hepatic impairment |
rifabutin | telithromycin |
increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with Itraconazole Capsulesmay increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes. |
| Anticoagulants and Antiplatelet Drugs |
ticagrelor | apixaban, rivaroxaban | coumarins, cilostazol, dabigatran |
|
| Anticonvulsants | carbamazepine | concentrations’. |
||
| Antidiabetics | repaglinide,saxagliptin |
|||
| Antihelmintics and Antiprotozoals |
praziquantel | |||
| Antimigraine Drugs | ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine) |
eletriptan | Itraconazole Capsules may increase the risk of ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. |
|
| Antineoplastics | irinotecan | axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib,trabectedin |
bortezomib, busulphan, docetaxel, erlotinib, gefitinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids |
|
| Antipsychotics, Anxiolytics and Hypnotics |
lurasidone, oral midazolam, pimozide, triazolam |
alprazolam,aripiprazole,buspirone,diazepam,haloperidol,midazolam IV,perospirone,quetiapine,ramelteon,risperidone |
Itraconazole Capsules and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. |
|
| Antivirals | simeprevir | maraviroc,indinavir,ritonavir,saquinavir |
concentrations’. |
|
| Beta Blockers | nadolol | |||
| Calcium Channel Blockers |
felodipine,nisoldipine |
other dihydropyridines,verapamil |
co-administered with Itraconazole Capsules may increase the risk of congestive heart failure. dihydropyridine calcium channel blockers. |
|
| Cardiovascular Drugs, Miscellaneous |
Ivabradine, ranolazine |
aliskiren, sildenafil, for the treatment of pulmonary hypertension |
bosentan, riociguat |
increase in plasma concentrations of ranolazine when coadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QTc prolongation. |
| Diuretics | eplerenone |
increase in plasma concentrations f eplerenone when coadministered with Itraconazole Capsules may increase the risk of hyperkalemia and hypotension. |
||
| Gastrointestinal Drugs |
cisapride | aprepitant | cisapride when oadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QTc prolongation. |
|
| Immunosuppressants | everolimus, temsirolimus |
budesonide,ciclesonide,cyclosporine,dexamethasone,fluticasone,methylprednisolone,rapamycin (also known as sirolimus),tacrolimus |
||
| Lipid Regulating Drugs |
lovastatin, simvastatin |
atorvastatin | The potential increase in plasma concentrations of atorvastatin,lovastatin, and simvastatin when coadministered with Itraconazole Capsules may increase the risk of skeletal muscle toxicity,including rhabdomyolysis. |
|
| Respiratory Drugs | salmeterol | |||
| Urological Drugs | fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment |
darifenacin, vardenafil |
Fesoterodine, oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine |
|
| Other | colchicine, in subjects with renal or hepatic impairment |
colchicines, conivaptan, tolvaptan |
cinacalcet, |
colchicine when coadministered with Itraconazole Capsules may increase the risk of potentially fatal adverse events. |
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| Atazanavir/Ritonavir* | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* Fosamprenavir/Ritonavir* |
↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* | ↓ Indinavir | The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* | ↓Lopinavir | Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir | The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
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||
| Efavirenz* Delavirdine Etravirine Rilpivirine |
↓ Efavirenz | The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
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|
Methadone* |
↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Clarithromycin* Rifabutin* Rifampin* |
↓ Clarithromycin ↑ 14-OH clarithromycin ↑ Rifabutin ↓ Nevirapine |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. | Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* Ketoconazole* Itraconazole |
↑Nevirapine ↓ Ketoconazole ↓ Itraconazole |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. | Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
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Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
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Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
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Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
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Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| * The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. | ||
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| Anticoagulants
|
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
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| Antiplatelet Agents
|
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
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| Nonsteroidal Anti-Inflammatory Agents
|
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
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| Serotonin Reuptake Inhibitors
|
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone
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|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin | Monitor phenytoin level ( |
| Methotrexate | Monitor for methotrexate toxicity ( |
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine | Decreased Ciprofloxacin Tablets, USP absorption. Take 2 hours before or 6 hours after Ciprofloxacin Tablets, USP ( |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
| |
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| Concentration Increase |
Increase |
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| Quinidine | NA | 54-83% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. |
| Ritonavir | NA | 86% | |
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| Amiodarone | 17% | 40% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. |
| Propafenone | 28% | 29% | |
| Quinine | NA | 34-38% | |
| Spironolactone | NA | 44% | |
| Verapamil | NA | 24% | |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Specific Drugs Reported | |||
| also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone |
cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate |
6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone |
propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage |
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| Known CYP2D6 Poor Metabolizers |
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| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| quinupristin/ | colchicine | |||
| voriconazole | dalfopristin | danazol | ||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
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| Drug | Type of Interaction | Effect** |
| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day. | 25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine | Similar to cimetidine |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Theophylline decreases phenytoin absorption. | ||
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
| ↓ = Decreased (induces lamotrigine glucuronidation). |
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| ↑ = Increased (inhibits lamotrigine glucuronidation). |
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| ? = Conflicting data. |
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|
Lamotrigine or Concomitant Drug |
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|
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
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? carbamazepine epoxide |
lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
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approximately 40%. |
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approximately 40%. |
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approximately 40%. |
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? valproate |
slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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The concomitant use of CONZIP and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of CONZIP is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression |
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If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering CONZIP dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation. |
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Quinidine, fluoxetine, paroxetine and bupropion |
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The concomitant use of CONZIP and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of CONZIP is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of CONZIP until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the CONZIP dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
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The concomitant use of CONZIP and CYP3A4 inducers can decrease the plasma concentration of tramadol, After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase |
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If concomitant use is necessary, consider increasing the CONZIP dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider CONZIP dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of CONZIP and carbamazepine is not recommended. |
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Rifampin, carbamazepine, phenytoin |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, , antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue CONZIP if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome |
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Do not use CONZIP in patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of CONZIP and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of CONZIP and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when CONZIP is used concomitantly with anticholinergic drugs. |
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Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity. |
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Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed. |
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Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times. |
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Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed. |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see |
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Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see |
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The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see |
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The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended. |
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Concomitant use of mefenamic acid and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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In a single dose study (n=6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively. |
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Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events. |
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See prescribing information for voriconazole. |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 50 mg (95% CI) |
|---|---|
| Supine | 9.08 (5.48, 12.68) |
| Standing |
11.62 (7.34, 15.90) |
|
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| Phenytoin
|
NCor25%increase
a
|
48%decrease
|
| Carbamazepine(CBZ)
|
NC
|
40%decrease
|
| CBZepoxide
b
|
NC
|
NE
|
| Valproic acid
|
11%decrease
|
14%decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NCatTPM dosesupto400 mg/day
|
13%decrease
|
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| |
|
| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
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Norepinephrine Dopamine |
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If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. |
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Naproxen may decrease platelet aggregation and prolong bleeding time. |
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This effect should be kept in mind when bleeding times are determined. |
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The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. |
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Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. |
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Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). |
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This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined. |
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| DRUG | DESCRIPTION OF INTERACTION |
| Sulfonylureas | Hypoglycemia potentiated. |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. |
| Oral Anticoagulants | Increased bleeding. |
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atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
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fibrates, gemfibrozil |
||
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digoxin |
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↑ Nevirapine |
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Fosamprenavir/Ritonavir* |
↑Nevirapine ↓Amprenavir ↑Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
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A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
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↓Nelfinavir Cmin |
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Delavirdine Etravirine Rilpivirine |
|
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
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Methadone* |
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Amiodarone, disopyramide, lidocaine |
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Clarithromycin* Rifabutin* Rifampin* |
↑14-OH clarithromycin ↑Rifabutin ↓ Nevirapine |
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
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Fluconazole* Ketoconazole* Itraconazole |
↓ Ketoconazole ↓ Itraconazole |
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
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Diltiazem, nifedipine, verapamil |
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Cyclophosphamide |
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Ergotamine |
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Cisapride |
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Fentanyl |
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Ethinyl estradiol and Norethindrone* |
↓ Norethindrone |
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| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
| Theophylline |
Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents |
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin |
Monitor phenytoin level ( |
| Methotrexate |
Monitor for methotrexate toxicity ( |
| Cyclosporine |
May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( |
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| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine
|
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
|
| Warfarin
|
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
|
| Antidiabetic agents
|
Carefully monitor blood glucose (
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| *Not administered but an active metabolite of carbamazepine. | ||
| **No significant effect. | ||
| AED Coadministered |
AED Concentration |
Felbatol® Concentration |
| Phenytoin | ↑ | ↓ |
| Valproate | ↑ | ↔** |
| Carbamazepine (CBZ) *CBZ epoxide |
↓ ↑ |
↓ |
| Phenobarbital | ↑ | ↓ |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (> 1 quart daily) |
| |
|
| Valproic acid | Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects ( |
| Probenecid | Reduces renal clearance of doripenem, resulting in increased doripenem concentrations ( |
| Drugs metabolized by cytochrome P450 enzymes | Doripenem neither inhibits nor induces major cytochrome P450 enzymes ( |
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| a Should be administered at least 4 hours prior to WELCHOL | |
|
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an |
|
| c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL. | |
| Drugs with a known interaction with colesevelam | Cyclosporinec, glyburidea, levothyroxinea, and oral contraceptives containing ethinyl estradiol and norethindronea |
| Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL | phenytoina, warfarinb |
| Drugs that do not interact with colesevelam based on |
cephalexin, ciprofloxacin, digoxin, warfarinb fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol
|
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone
|
Do not exceed 10 mg simvastatin daily
|
| Amiodarone, amlodipine, ranolazine
|
Do not exceed 20 mg simvastatin daily
|
| Lomitapide
|
For patients with HoFH, do not exceed 20 mg simvastatin daily*
|
| Grapefruit juice
|
Avoid grapefruit juice
|
| albuterol, | lomefloxacin |
| systemic and inhaled | mebendazole |
| amoxicillin | medroxyprogesterone |
| ampicillin, | methylprednisolone |
| with or without sulbactam | metronidazole |
| atenolol | metoprolol |
| azithromycin | nadolol |
| Caffeine, | nifedipine |
| dietary ingestion | nizatidine |
| cefactor | norfloxacin |
| co-trimoxazole | ofloxacin |
| (trimethoprim and | omeprazole |
| sulfamethoxazole) | prednisone, prednisolone |
| diltiazem | ranitidine |
| dirithromycin | rifabutin |
| enflurane | roxithromycin |
| famotidine | sorbitol |
| felodipine | (purgative doses do not |
| finasteride | inhibit theophylline |
| hydrocortisone | absorption) |
| isoflurane | sucralfate |
| isoniazid terbutaline, | systemic |
| isradipine | terfenadine |
| influenza vaccine | tetracycline |
| ketoconazole | tocainide |
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Hepatitis C protease inhibitor (boceprevir) |
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Decreased exposure of omeprazole when used concomitantly with strong inducers |
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St. John’s Wort, rifampin: Avoid concomitant use with omeprazole Ritonavir-containing products: see prescribing information for specific drugs. |
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Increased exposure of omeprazole |
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Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole. |
| * For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. | |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily* |
| Grapefruit juice |
Avoid grapefruit juice |
| Interacting Drug | Interaction |
|---|---|
| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin | Monitor phenytoin level ( |
| Methotrexate | Monitor for methotrexate toxicity ( |
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine ( |
| AED Coadministered | Dose of AED (mg/day) |
Oxcarbazepine Tablets Dose (mg/day) |
Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval) |
Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc |
40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc |
18% decrease [CI: 13% decrease, 40% decrease] |
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| Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol |
Contraindicated with VYTORIN |
| Verapamil, diltiazem, dronedarone | Do not exceed 10/10 mg VYTORIN daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 10/20 mg VYTORIN daily |
| Lomitapide | For patients with HoFH, do not exceed 10/20 mg VYTORIN daily |
| Grapefruit juice | Avoid grapefruit juice |
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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The concomitant use of beta-blockers and Glucagon for Injection may increase the risk of a temporary increase in heart rate and blood pressure. |
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The increase in blood pressure and heart rate may require therapy in patients with coronary artery disease. |
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Insulin reacts antagonistically towards glucagon. |
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Monitor blood glucose when Glucagon for Injection is used as a diagnostic aid in diabetes patients. |
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The concomitant use of indomethacin and Glucagon for Injection may lead to hypoglycemia. |
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Monitor blood glucose levels during glucagon treatment of patients taking indomethacin. |
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The concomitant use of anticholinergic drugs and Glucagon for Injection increase the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility. |
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Concomitant use is not recommended. |
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Glucagon may increase the anticoagulant effect of warfarin. |
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Monitor patients for unusual bruising or bleeding, as adjustments in warfarin dosage may be required. |
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| Tolbutamide; Sulfonylureas | Hypoglycemia potentiated |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result |
| Oral Anticoagulant | Increased bleeding |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ |
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During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidibetic agents | Carefully monitor blood glucose ( |
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The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
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Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue
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selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
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Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
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Concomitant use of pimozide and sertraline hydrochloride is contraindicated
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The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
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Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs
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other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
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The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
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Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio
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aspirin, clopidogrel, heparin, warfarin
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Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma
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Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
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warfarin
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Sertraline hydrochloride is a CYP2D6 inhibitor
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Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
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propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
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Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
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Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
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phenytoin, fosphenytoin
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| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose |
| AED Co-administered | AED Concentration | Topiramate Concentration |
|---|---|---|
| NC = Less than 10% change in plasma concentration. | ||
| NE = Not Evaluated | ||
| Phenytoin | NC or 25% increase
|
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide
|
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
|
|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. |
|
| Allopurinol |
|
25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. |
|
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increase theophylline clearance. | 20% increase |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20 to 40% decrease |
| Sulfinpyrazone | Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% increase |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33 to 100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide
|
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
|
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
|
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
(mg) |
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Cimetidine | 600 twice daily, 6 days |
400 single dose | 12 | 1.07 (0.77, 1.49) |
0.98 (0.81, 1.19) |
0.82 (0.69, 0.99) |
| Clarithromycin | 500 q12h, 7 days |
800 three times daily, 7 days |
10 | 1.08 (0.85, 1.38) |
1.19 (1.00, 1.42) |
1.57 (1.16, 2.12) |
| Delavirdine | 400 three times daily | 400 three times daily, 7 days |
28 | 0.64 (0.48, 0.86) |
No significant change |
2.18 (1.16, 4.12) |
| Delavirdine | 400 three times daily | 600 three times daily, 7 days |
28 | No significant change | 1.53 (1.07, 2.20) |
3.98 (2.04, 7.78) |
| Efavirenz |
600 once daily, 10 days |
1000 three times daily, 10 days |
20 | |||
| After morning dose | No significant change |
0.67 (0.61, 0.74) |
0.61 (0.49, 0.76) |
|||
| After afternoon dose | No significant change |
0.63 (0.54, 0.74) |
0.48 (0.43, 0.53) |
|||
| After evening dose | 0.71 (0.57, 0.89) |
0.54 (0.46, 0.63) |
0.43 (0.37, 0.50) |
|||
| Fluconazole |
400 once daily, 8 days |
1000 three times daily, 7 days | 11 | 0.87 (0.72, 1.05) |
0.76 (0.59, 0.98) |
0.90 (0.72, 1.12) |
| Grapefruit Juice | 8 oz. | 400 single dose | 10 | 0.65 (0.53, 0.79) |
0.73 (0.60, 0.87) |
0.90 (0.71, 1.15) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 7 days | 11 | 0.95 (0.88, 1.03) |
0.99 (0.87, 1.13) |
0.89 (0.75, 1.06) |
| Itraconazole | 200 twice daily, 7 days |
600 three times daily, 7 days |
12 | 0.78 (0.69, 0.88) |
0.99 (0.91, 1.06) |
1.49 (1.28, 1.74) |
| Ketoconazole | 400 once daily, 7 days |
600 three times daily, 7 days |
12 | 0.69 (0.61, 0.78) |
0.80 (0.74, 0.87) |
1.29 (1.11, 1.51) |
| 400 once daily, 7 days |
400 three times daily, 7 days |
12 | 0.42 (0.37, 0.47) |
0.44 (0.41, 0.48) |
0.73 (0.62, 0.85) |
|
| Methadone | 20-60 once daily in the morning, 8 days |
800 three times daily, 8 days |
10 | See text below for discussion of interaction. | ||
| Quinidine | 200 single dose | 400 single dose | 10 | 0.96 (0.79, 1.18) |
1.07 (0.89, 1.28) |
0.93 (0.73, 1.19) |
| Rifabutin | 150 once daily in the morning, 10 days |
800 three times daily, 10 days |
14 | 0.80 (0.72, 0.89) |
0.68 (0.60, 0.76) |
0.60 (0.51, 0.72) |
| Rifabutin | 300 once daily in the morning, 10 days |
800 three times daily, 10 days |
10 | 0.75 (0.61, 0.91) |
0.66 (0.56, 0.77) |
0.61 (0.50, 0.75) |
| Rifampin | 600 once daily in the morning, 8 days |
800 three times daily, 7 days |
12 | 0.13 (0.08, 0.22) |
0.08 (0.06, 0.11) |
Not Done |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 16 |
See text below for discussion of interaction. | ||
| Ritonavir | 200 twice daily, 14 days |
800 twice daily,14 days |
9, 16 |
See text below for discussion of interaction. | ||
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| St. John's wort ( standardized to 0.3 % hypericin) |
300 three times daily with meals, 14 days |
800 three times daily | 8 | Not Available | 0.46 (0.34, 0.58) |
0.19 (0.06, 0.33) |
| Stavudine (d4T) |
40 twice daily, 7 days |
800 three times daily, 7 days |
11 | 0.95 (0.80, 1.11) |
0.95 (0.80, 1.12) |
1.13 (0.83, 1.53) |
| Trimethoprim/ Sulfamethoxazole |
800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 four times daily, 7 days |
12 | 1.12 (0.87, 1.46) |
0.98 (0.81, 1.18) |
0.83 (0.72, 0.95) |
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days |
12 | 1.06 (0.91, 1.25) |
1.05 (0.86, 1.28) |
1.02 (0.77, 1.35) |
| Zidovudine/ Lamivudine (3TC) |
200/150 three times daily, 7 days | 800 three times daily, 7 days |
6, 9 |
1.05 (0.83, 1.33) |
1.04 (0.67, 1.61) |
0.98 (0.56, 1.73) |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| * The interaction between immediate-release nevirapine and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets. | ||
|
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|
||
| Atazanavir/Ritonavir* |
↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* Fosamprenavir/Ritonavir* |
↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* |
↓ Indinavir |
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* |
↓Lopinavir |
Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* |
↓ Nelfinavir M8 Metabolite ↓ Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir |
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated |
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
|
||
| Efavirenz* |
↓ Efavirenz |
The appropriate doses of these combinations with respect to safety and efficacy have not been established. |
| Delavirdine Etravirine Rilpivirine |
|
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
|
|
||
| Boceprevir |
Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. |
Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy. |
| Telaprevir |
Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. |
Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events. |
|
|
||
|
Methadone* |
↓ Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Clarithromycin* |
↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Rifabutin* |
↑ Rifabutin |
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin* |
↓ Nevirapine |
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* |
↑ Nevirapine |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Ketoconazole* |
↓ Ketoconazole |
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Itraconazole |
↓ Itraconazole |
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine extended-release tablets, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception. When oral contraceptives are used for hormonal regulation during nevirapine extended-release tablets therapy, the therapeutic effect of the hormonal therapy should be monitored. |
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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See |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily* |
| Grapefruit juice | Avoid grapefruit juice |
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Decreased exposure of omeprazole when used concomitantly with strong inducers
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St. John’s Wort, rifampin: Avoid concomitant use with omeprazole
Ritonavir-containing products: see prescribing information for specific drugs. |
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Increased exposure of omeprazole
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Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered.
See prescribing information for voriconazole. |
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| Atazanavir/Ritonavir* | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* Fosamprenavir/Ritonavir* |
↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* | ↓ Indinavir | The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* | ↓Lopinavir | Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir | The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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| Efavirenz* Delavirdine Etravirine Rilpivirine |
↓ Efavirenz | The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
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||
|
Methadone* |
↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Clarithromycin* Rifabutin* Rifampin* |
↓ Clarithromycin ↑ 14-OH clarithromycin ↑ Rifabutin ↓ Nevirapine |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. | Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* Ketoconazole* Itraconazole |
↑Nevirapine ↓ Ketoconazole ↓ Itraconazole |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. | Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| * The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. | ||
|
** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed. |
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| Theophylline |
Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7) |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7) |
| Antidiabetic agents |
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7) |
| Phenytoin |
Monitor phenytoin level (7) |
| Methotrexate |
Monitor for methotrexate toxicity (7) |
| Cyclosporine |
May increase serum creatinine. Monitor serum creatinine (7) |
| Multivalent cation- containing products including antacids, metal cations or didanosine |
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7) |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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|
Avoid atorvastatin
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| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily
|
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)
|
Do not exceed 40 mg atorvastatin daily |
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| Coadministered Drug
|
Dosing Schedule
|
|
Effect on Active
Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose
Recommendation |
|
|
Coadministered Drug
|
Risperidone
|
AUC
|
C
m
a
x
|
|
| Enzyme (CYP2D6)
Inhibitors |
|
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|
|
| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice
daily |
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day
|
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
-
|
Re-evaluate dosing.
|
|
|
20 mg/day
|
4 mg/day
|
1.6
|
-
|
Do not exceed 8 mg/day
|
|
|
40 mg/day
|
4 mg/day
|
1.8
|
-
|
|
| Enzyme (CYP3A/
PgP inducers) |
|
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|
|
| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards.
Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)
Inhibitors |
|
|
|
|
|
| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not
needed |
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not
needed |
| Erythromycin
|
500 mg four times
daily |
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not
needed |
| Other Drugs
|
|
|
|
|
|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not
needed |
|
|
|
| Known CYP2D6 Poor Metabolizers |
Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors |
Administer a quarter of usual dose |
| Strong CYP2D6 |
Administer half of usual dose |
| Strong CYP2D6 inhibitors |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers |
Double usual dose over 1 to 2 weeks |
| Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV). |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
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Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( |
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Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology ( |
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During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( |
|
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
| NA – Not available/reported | |||
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Concentration Increase |
Increase |
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| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
|
NC or 25% increase
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
|
|
|
|
|
|
|
|
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
|
|
|
|
|
|
Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
|
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|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. |
|
|
|
|
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|
|
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
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|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). |
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. | |
|
|
|
| Calcium Carbonate
Ferrous Sulfate |
Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents. |
| Orlistat | Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function. |
| Bile Acid Sequestrants
- Colesevelam - Cholestyramine - Colestipol Ion Exchange Resins - Kayexalate - Sevelamer |
Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels. |
| Other drugs:
Proton Pump Inhibitors Sucralfate Antacids - Aluminum & Magnesium Hydroxides - Simethicone |
Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately. |
| |
|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
|
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|---|---|---|
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|
| Drug | Description |
|---|---|
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism |
| Ammonium Sulfate | Increases plasma salicylate level |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary digestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
(CYP450 Induction) |
|
|
|
|
|
|
|
(CYP450 Induction) |
|
|
|
|
|
|
|
(CYP450 Induction) |
|
|
|
(CYP450 Induction) |
|
|
|
(CYP450 Induction) |
|
|
|
(CYP450 inducer; P-gp inducer) |
|
|
|
containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
|
|
|
|
|
|
|
(CYP3A4 Inhibition) |
|
|
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|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Coadministered drug | Dosing regimen of coadministered drug | Dosing regimen of rifabutin | Study population (n) | Effect on rifabutin | Effect on coadministered drug | Recommendation |
|---|---|---|---|---|---|---|
| ↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change QD- once daily; BID- twice daily; TID – thrice daily ND - No Data AUC - Area under the Concentration vs. Time Curve; Cmax - Maximum serum concentration |
||||||
|
|
||||||
| Amprenavir | 1200 mg BID × 10 days | 300 mg QD × 10 days | Healthy male subjects (6) | ↑ AUC by 193%, ↑ Cmax by 119% |
↔ | Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions. |
| Delavirdine | 400 mg TID | 300 mg QD | HIV-infected patients (7) | ↑ AUC by 230%, ↑ Cmax by 128% |
↓ AUC by 80%, ↓ Cmax by 75%, ↓ Cmin by 17% |
|
| Didanosine | 167 or 250 mg BID × 12 days | 300 or 600 mg QD × 1 | HIV-infected patients (11) | ↔ | ↔ | |
| Fosamprenavir/ ritonavir | 700 mg BID plus ritonavir 100 mg BID × 2 weeks | 150 mg every other day × 2 weeks | Healthy subjects (15) | ↔ AUC ↓ Cmax by 15% |
↑ AUC by 35% ↑ Cmax by 36%, ↑ Cmin by 36%, |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination. |
| Indinavir | 800 mg TID × 10 days | 300 mg QD × 10 days | Healthy subjects (10) | ↑ AUC by 173%, ↑ Cmax by 134% |
↓ AUC by 34%, ↓ Cmax by 25%, ↓ Cmin by 39% |
Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID. |
| Lopinavir/ ritonavir | 400/100 mg BID × 20 days | 150 mg QD × 10 days | Healthy subjects (14) | ↑ AUC by 203% ↓ Cmax by 112% |
↔ | Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Saquinavir/ ritonavir | 1000/100 mg BID × 14 or 22 days | 150 mg every 3 days × 21–22 days | Healthy subjects | ↑ AUC by 53% ↑ Cmax by 88% (n=11) |
↓ AUC by 13%, ↓ Cmax by 15%, (n=19) |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions. |
| Ritonavir | 500 mg BID × 10 days | 150 mg QD × 16 days | Healthy subjects (5) | ↑ AUC by 300%, ↑ Cmax by 150% |
ND | Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Tipranavir/ ritonavir | 500/200 BID × 15 doses | 150 mg single dose | Healthy subjects (20) | ↑ AUC by 190%, ↑ Cmax by 70% |
↔ | Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Nelfinavir | 1250 mg BID × 7–8 days | 150 mg QD × 8 days | HIV-infected patients (11) | ↑ AUC by 83%, ↑ Cmax by 19% |
↔ | Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID |
| Zidovudine | 100 or 200 mg q4h | 300 or 450 mg QD | HIV-infected patients (16) | ↔ | ↓ AUC by 32%, ↓ Cmax by 48%, |
Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary. |
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| Fluconazole | 200 mg QD × 2 weeks | 300 mg QD × 2 weeks | HIV-infected patients (12) | ↑ AUC by 82%, ↑ Cmax by 88% |
↔ | Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend MYCOBUTIN use if toxicity is suspected. |
| Posaconazole | 200 mg QD × 10 days | 300 mg QD × 17 days | Healthy subjects (8) | ↑ AUC by 72%, ↑ Cmax by 31% |
↓ AUC by 49%, ↓ Cmax by 43% |
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy. |
| Itraconazole | 200 mg QD | 300 mg QD | HIV-Infected patients (6) | ↑ |
↓ AUC by 70%, ↓ Cmax by 75%, |
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following co-administration of rifabutin (300 mg QD) with itraconazole (600–900 mg QD). |
| Voriconazole | 400 mg BID × 7 days (maintenance dose) | 300 mg QD × 7 days | Healthy male subjects (12) | ↑ AUC by 331%, ↑ Cmax by 195% |
↑ AUC by ~100%, ↑ Cmax by ~100% |
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| Dapsone | 50 mg QD | 300 mg QD | HIV-infected patients (16) | ND | ↓ AUC by 27 –40% | |
| Sulfamethoxazole- Trimethoprim | 800/160 mg | 300 mg QD | HIV-infected patients (12) | ↔ | ↓ AUC by 15–20% | |
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| Azithromycin | 500 mg QD × 1 day, then 250 mg QD × 9 days | 300 mg QD | Healthy subjects (6) | ↔ | ↔ | |
| Clarithromycin | 500 mg BID | 300 mg QD | HIV-infected patients (12) | ↑ AUC by 75% | ↓ AUC by 50% | Monitor for rifabutin associated adverse events. Reduce dose or suspend use of MYCOBUTIN if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin |
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| Ethambutol | 1200 mg | 300 mg QD × 7 days | Healthy subjects (10) | ND | ↔ | |
| Isoniazid | 300 mg | 300 mg QD × 7 days | Healthy subjects (6) | ND | ↔ | |
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| Methadone | 20 – 100 mg QD | 300 mg QD × 13 days | HIV-infected patients (24) | ND | ↔ | |
| Ethinylestradiol (EE)/Norethindrone (NE) | 35 mg EE / 1 mg NE × 21 days | 300 mg QD × 10 days | Healthy female subjects (22) | ND | EE: ↓ AUC by 35%, ↓ Cmax by 20% NE: ↓ AUC by 46% |
Patients should be advised to use additional or alternative methods of contraception. |
| Theophylline | 5 mg/kg | 300 mg × 14 days | Healthy subjects (11) | ND | ↔ | |
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|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| NA = Not available/reported | |||
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Concentration Increase |
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| DRUG | DESCRIPTION OF INTERACTION |
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. |
| Acidifying Agents | Increases plasma salicylate level. |
| Alkalizing Agents | Decreased plasma salicylate levels. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
These drugs may increase serum thyroxine-binding globulin (TBG) concentration. |
| Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
These drugs may decrease serum TBG concentration. |
| Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations. | |
| Salicylates (> 2 g/day) | Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%. |
| Other drugs: Carbamazepine Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates |
These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters. |
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| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
* Results based on ** Results based on *** Results based on **** Non-Steroidal Anti-Inflammatory Drug ***** Non-Nucleoside Reverse Transcriptase Inhibitors |
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(Mechanism of Interaction by Voriconazole) |
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| Sirolimus* (CYP3A4 Inhibition) |
Significantly Increased |
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| Rifabutin* (CYP3A4 Inhibition) |
Significantly Increased |
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| Efavirenz (400 mg q24h)** (CYP3A4 Inhibition) Efavirenz (300 mg q24h)** (CYP3A4 Inhibition) |
Significantly Increased Slight Increase in |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
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| High-dose Ritonavir (400 mg q12h)** (CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)** |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ
Slight Decrease in Ritonavir Cmax and AUCτ |
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
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| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
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| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
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| Cyclosporine* (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax
|
When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
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| Methadone*** (CYP3A4 Inhibition) |
Increased |
Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
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| Fentanyl (CYP3A4 Inhibition) |
Increased |
Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole |
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| Alfentanil (CYP3A4 Inhibition) |
Significantly Increased |
Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablet. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ |
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| Oxycodone (CYP3A4 Inhibition) |
Significantly Increased |
Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole |
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| NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition) |
Increased |
Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ |
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| Tacrolimus* (CYP3A4 Inhibition) |
Significantly Increased |
When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole |
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| Phenytoin* (CYP2C9 Inhibition) |
Significantly Increased |
Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
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| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** |
Increased |
Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
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| Warfarin* (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased |
Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
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| Omeprazole* (CYP2C19/3A4 Inhibition) |
Significantly Increased |
When initiating therapy with voriconazole |
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| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment for indinavir when coadministered with voriconazole tablets Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors |
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| Other NNRTIs***** (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
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| Benzodiazepines (CYP3A4 Inhibition) |
|
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
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| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
|
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
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| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
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Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
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| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
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| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
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| Everolimus (CYP3A4 Inhibition) |
Not Studied |
Concomitant administration of voriconazole and everolimus is not recommended. |
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(increased and decreased) |
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Five-fold increase in duloxetine exposure |
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of serum half-life |
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Agents |
sives |
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derivatives (e.g., bezafibrate, fenofibrate) methotrexate |
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Drug |
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↑ Zidovudine |
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↔ MMF (in patients with normal renal function) |
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↑ Didanosine |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide
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Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide
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Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
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Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin
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Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
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Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
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Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
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| Zidovudine | ↓ Ganciclovir ↑ Zidovudine |
Zidovudine and valganciclovir each have the potential to cause neutropenia and anemia |
| Probenecid | ↑ Ganciclovir | Patients taking probenecid and valganciclovir should be monitored for evidence of ganciclovir toxicity |
| Mycophenolate Mofetil (MMF) | ↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) |
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase |
| Didanosine | ↓ Ganciclovir ↑ Didanosine |
Patients should be closely monitored for didanosine toxicity |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
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Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate |
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Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Clinical Impact: | Naproxen may decrease platelet aggregation and prolong bleeding time. |
| Intervention: | This effect should be kept in mind when bleeding times are determined. |
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| Clinical Impact: | The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. |
| Intervention: | Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. |
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| Clinical Impact: | Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). |
| Intervention: | This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined. |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| AED Coadministered |
AED Concentration |
Topiramate Concentration |
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 15% increase |
| NC = Less than 10% change in plasma concentration AED = Antiepileptic drug NE = Not Evaluated TPM = Topiramate |
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Norepinephrine Dopamine |
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The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression |
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If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation. |
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Quinidine, fluoxetine, paroxetine and bupropion |
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The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
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The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase |
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If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended. |
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Rifampin, carbamazepine, phenytoin |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome |
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Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets are used concomitantly with anticholinergic drugs. |
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Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity. |
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Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed. |
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Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times. |
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Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed. |
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| Clinical Impact: | Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. | |
| Intervention: |
Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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| Clinical Impact: |
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
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| Intervention: |
Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
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| Clinical Impact: | NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. | |
| Intervention: |
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [
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| Clinical Impact: |
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [
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| Intervention: |
Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [
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| Clinical Impact: | The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. | |
| Intervention: | During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. | |
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| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. | |
| Intervention: | During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. | |
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| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). | |
| Intervention: | During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity. | |
| Intervention: | During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. | |
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| Clinical Impact: |
Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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| Intervention: | The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). | |
| Intervention: | During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. | |
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| Clinical Impact: | When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. | |
| Intervention: | During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. | |
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Dofetilide | Concomitant administration with digoxin was associated with a higher rate of torsades de pointes. |
| Moricizine | Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction. | |
| Sotalol | Proarrhythmic events even more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving dioxin. | |
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Teriparatide | Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. |
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Thyroid | Treatment of hyperthyroidism in patients taking digoxin may increase the dose requirements of digoxin. |
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Epinepherine | Can increase the risk of cardiac arrhythmias. |
| Norepinephrine | ||
| Dopamine | ||
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Succinylcholine | May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin. |
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Calcium | If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. |
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Additive effects on AV node conduction can result in complete heart block. | |
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| Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24) | ||
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(Peak plasma concentration) |
(Extent of systemic exposure) |
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Antipsychotics | pimozide |
| Antiarrhythmics | dofetilide, quinidine |
| Benzodiazepines | oral midazolam |
| Calcium Channel Blockers | Nisoldipine, felodipine |
| Ergot Alkaloids | dihydroergotamine, ergotamine, ergometrine (ergonovine), methylergometrine (methylergonovine) |
| Gastrointestinal Motility Agents | cisapride |
| HMG CoA-Reductase Inhibitors | lovastatin, simvastatin |
| Opiate Analgesics | levacetylmethadol (levomethadyl), methadone |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| CYP2C9
|
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
|
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
|
| CYP1A2
|
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
|
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
|
| CYP3A4
|
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
|
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide
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| Estrogen-containing oral
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine
|
Decreased lamotrigine levels
approximately 50%. |
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|
↓ levonorgestrel
|
Decrease in levonorgestrel component by 19%.
|
| Carbamazepine (CBZ) and
CBZ epoxide |
↓ lamotrigine
|
Addition of carbamazepine decreases lamotrigine
concentration approximately 40%. |
|
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? CBZ epoxide
|
May increase CBZ epoxide levels
|
| Phenobarbital/Primidone
|
↓ lamotrigine
|
Decreased lamotrigine
concentration approximately 40%. |
| Phenytoin (PHT)
|
↓ lamotrigine
|
Decreased lamotrigine
concentration approximately 40% |
| Rifampin
|
↓ lamotrigine
|
Decreased lamotrigine AUC
approximately 40% |
| Valproate
|
↑ lamotrigine
|
Increased lamotrigine concentrations slightly
more than 2-fold. |
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? valproate
|
Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Monoamine Oxidase Inhibitors (MAOIs) | The concomitant use of MAOIs and serotonergic drugs including VIIBRYD increases the risk of serotonin syndrome. | VIIBRYD is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue |
| Other Serotonergic Drugs | The concomitant use of serotonergic drugs including VIIBRYD and other serotonergic drugs increases the risk of serotonin syndrome. | Monitor patients for signs and symptoms of serotonin syndrome, particularly during VIIBRYD initiation. If serotonin syndrome occurs, consider discontinuation of VIIBRYD and/or concomitant serotonergic drugs |
| Antiplatelet Agents and Anticoagulants | Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with VIIBRYD may potentiate the risk of bleeding. | Inform patients of the increased risk of bleeding with the concomitant use of VIIBRYD and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing VIIBRYD |
| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole) | The concomitant use of VIIBRYD and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of VIIBRYD alone |
The VIIBRYD dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor |
| Strong CYP3A4 Inducers (e.g., carbamazepine, phenytoin, rifampin) |
The concomitant use of VIIBRYD and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of VIIBRYD alone |
Based on clinical response, consider increasing the dosage of VIIBRYD, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days |
| Digoxin | Digoxin is a narrow therapeutic index drug. Concomitant use of VIIBRYD increased digoxin concentrations |
Measure serum digoxin concentrations before initiating concomitant use of VIIBRYD. Continue monitoring and reduce digoxin dose as necessary. |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Sulfonylureas | Hypoglycemia potentiated. | ||
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. | ||
| Oral Anticoagulants | Increased bleeding. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. | ||
| Acidifying Agents | Increases plasma salicylate levels. | ||
| Alkanizing Agents | Decreased plasma salicylate levels. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. | ||
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. | ||
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. | ||
| The following alterations of laboratory tests have been reported during salicylate therapy: | |||
| LABORATORY TESTS | EFFECT OF SALICYLATES | ||
| Thyroid Function | Decreased PBI; increased t3 uptake. | ||
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). | ||
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. | ||
| Acetone ketone bodies | False positive FeCI3 in Gerhardt reaction; red color persists with boiling. | ||
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. | ||
| Vanilmandelic acid | False reduced values. | ||
| Uric Acid | May increase or decrease depending on dose. | ||
| Prothrombin | Decreased levels; slightly increased prothrombin time. | ||
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| Interacting Agents | Prescribing Recommendations |
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone |
Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil |
Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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See |
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| *Change relative to reference |
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(Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Recommendation |
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Re-evaluate dosing. Do not exceed 8 mg/day |
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Re-evaluate dosing. Do not exceed 8 mg/day |
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Titrate dose upwards. Do not exceed twice the patient’s usual dose |
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Do not co-administer the intravenous formulation in the same IV line with an multivalent cation, e.g., magnesium ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
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Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant uses of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
|
Monitor patients with concomitant use of indomethacin capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
|
|
Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
|
|
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin capsules and triamterene should not be administered together. Both Indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. |
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|
Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [ |
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The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
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During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. |
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Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. |
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|
During the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. |
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| Atazanavir/Ritonavir* | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* | ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir* | ↓ Amprenavir ↑ Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* | ↓ Indinavir | The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* | ↓ Lopinavir | Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* | ↓ Nelfinavir M8 Metabolite ↓ Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir | The interaction between nevirapine and saquinavir/ritonavir has not been evaluated. | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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| Efavirenz* | ↓ Efavirenz | The appropriate doses of these combinations with respect to safety and efficacy have not been established. |
| Delavirdine Etravirine Rilpivirine |
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. | |
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|
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| Boceprevir | Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. | Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy. |
| Telaprevir | Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. | Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events. |
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Methadone* |
↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
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Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
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Clarithromycin* |
↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Rifabutin* | ↑ Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin* | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
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Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. | Use with caution and monitor virologic response and levels of anticonvulsants. |
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Fluconazole* |
↑ Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Ketoconazole* | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Itraconazole | ↓ Itraconazole | Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
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Warfarin |
Plasma concentrations may be increased. | Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
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Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
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Cyclophosphamide |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
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Ergotamine |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
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Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
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Cisapride |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
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Fentanyl |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
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Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Interacting Drug | Interaction |
|---|---|
| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin | Monitor phenytoin level ( |
| Methotrexate | Monitor for methotrexate toxicity ( |
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine ( |
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| Clinical Impact | Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. |
| Intervention | Do not administer MAS-ER Capsules concomitantly or within 14 days after discontinuing MAOI |
| Examples | selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
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| Clinical Impact | The concomitant use of MAS-ER Capsules and serotonergic drugs increases the risk of serotonin syndrome. |
| Intervention | Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during MAS-ER Capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the concomitant serotonergic drug(s) |
| Examples | selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort |
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| Clinical Impact | The concomitant use of MAS-ER Capsules and CYP2D6 inhibitors may increase the exposure of MAS-ER Capsules compared to the use of the drug alone and increase the risk of serotonin syndrome. |
| Intervention | Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during MAS-ER Capsules initiation and after a dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the CYP2D6 inhibitor |
| Examples | paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir |
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| Clinical Impact | Increase blood levels and potentiate the action of amphetamine. |
| Intervention | Co-administration of MAS-ER Capsules and gastrointestinal or urinary alkalinizing agents should be avoided. |
| Examples | Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g. acetazolamide, some thiazides). |
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| Clinical Impact | Lower blood levels and efficacy of amphetamines. |
| Intervention | Increase dose based on clinical response. |
| Examples | Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid). Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts). |
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| Clinical Impact | May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. |
| Intervention | Monitor frequently and adjust or use alternative therapy based on clinical response. |
| Examples | desipramine, protriptyline |
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| Clinical Impact | Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone. |
| Intervention | Monitor patients for changes in clinical effect and adjust therapy based on clinical response. |
| Examples | omeprazole |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | |
Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | |
Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate | |
Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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Monitor patients with concomitant use of CALDOLOR with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Concomitant use of CALDOLOR and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ CALDOLOR is not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of CALDOLOR with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of CADOLOR and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of CALDOLOR and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of CALDOLOR and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of CALDOLOR and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of CALDOLOR and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended. |
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Concomitant use of CALDOLOR and pemetrexed, may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of CALDOLOR and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
| Concomitant Drug Name or Drug Class | Clinical Rationale | Clinical Recommendation |
|---|---|---|
| Monoamine Oxidase Inhibitors (MAOIs) | Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. | Do not administer VYVANSE concomitantly or within 14 days after discontinuing MAOI treatment |
| Coadministered drug | Dosing regimen of coadministered drug | Dosing regimen of rifabutin | Study population (n) | Effect on rifabutin | Effect on coadministered drug | Recommendation |
|---|---|---|---|---|---|---|
| ↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change | ||||||
| QD- once daily; BID- twice daily; TID – thrice daily | ||||||
| ND - No Data | ||||||
| AUC - Area under the Concentration vs. Time Curve; Cmax - Maximum serum concentration | ||||||
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| Amprenavir | 1200 mg BID × 10 days | 300 mg QD × 10 days | Healthy male subjects (6) | ↑ AUC by 193%, ↑ Cmax by 119% |
↔ | Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions. |
| Delavirdine | 400 mg TID | 300 mg QD | HIV-infected patients (7) | ↑ AUC by 230%, ↑ Cmax by 128% |
↓ AUC by 80%, ↓ Cmax by 75%, ↓ Cmin by 17% |
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| Didanosine | 167 or 250 mg BID × 12 days | 300 or 600 mg QD × 1 | HIV-infected patients (11) | ↔ | ↔ | |
| Fosamprenavir/ ritonavir | 700 mg BID plus ritonavir 100 mg BID × 2 weeks | 150 mg every other day × 2 weeks | Healthy subjects (15) | ↔ AUC ↓ Cmax by 15% |
↑ AUC by 35% ↑ Cmax by 36%, ↑ Cmin by 36%, |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination. |
| Indinavir | 800 mg TID × 10 days | 300 mg QD × 10 days | Healthy subjects (10) | ↑ AUC by 173%, ↑ Cmax by 134% |
↓ AUC by 34%, ↓ Cmax by 25%, ↓ Cmin by 39% |
Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID. |
| Lopinavir/ ritonavir | 400/100 mg BID × 20 days | 150 mg QD × 10 days | Healthy subjects (14) | ↑ AUC by 203% ↓ Cmax by 112% |
↔ | Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Saquinavir/ ritonavir | 1000/100 mg BID × 14 or 22 days | 150 mg every 3 days × 21–22 days | Healthy subjects | ↑ AUC by 53% ↑ Cmax by 88% (n=11) |
↓ AUC by 13%, ↓ Cmax by 15%, (n=19) |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions. |
| Ritonavir | 500 mg BID × 10 days | 150 mg QD × 16 days | Healthy subjects (5) | ↑ AUC by 300%, ↑ Cmax by 150% |
ND | Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Tipranavir/ ritonavir | 500/200 BID × 15 doses | 150 mg single dose | Healthy subjects (20) | ↑ AUC by 190%, ↑ Cmax by 70% |
↔ | Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Nelfinavir | 1250 mg BID × 7–8 days | 150 mg QD × 8 days | HIV-infected patients (11) | ↑ AUC by 83%, ↑ Cmax by 19% |
↔ | Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID |
| Zidovudine | 100 or 200 mg q4h | 300 or 450 mg QD | HIV-infected patients (16) | ↔ | ↓ AUC by 32%, ↓ Cmax by 48%, |
Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary. |
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| Fluconazole | 200 mg QD × 2 weeks | 300 mg QD × 2 weeks | HIV-infected patients (12) | ↑ AUC by 82%, ↑ Cmax by 88% |
↔ | Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected. |
| Posaconazole | 200 mg QD × 10 days | 300 mg QD × 17 days | Healthy subjects (8) | ↑ AUC by 72%, ↑ Cmax by 31% |
↓ AUC by 49%, ↓ Cmax by 43% |
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy. |
| Itraconazole | 200 mg QD | 300 mg QD | HIV-Infected patients (6) | ↑ |
↓ AUC by 70%, ↓ Cmax by 75%, |
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following co-administration of rifabutin (300 mg QD) with itraconazole (600–900 mg QD). |
| Voriconazole | 400 mg BID × 7 days (maintenance dose) | 300 mg QD × 7 days | Healthy male subjects (12) | ↑ AUC by 331%, ↑ Cmax by 195% |
↑ AUC by ~100%, ↑ Cmax by ~100% |
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| Dapsone | 50 mg QD | 300 mg QD | HIV-infected patients (16) | ND | ↓ AUC by 27 –40% | |
| Sulfamethoxazole-Trimethoprim | 800/160 mg | 300 mg QD | HIV-infected patients (12) | ↔ | ↓ AUC by 15–20% | |
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| Azithromycin | 500 mg QD × 1 day, then 250 mg QD × 9 days | 300 mg QD | Healthy subjects (6) | ↔ | ↔ | |
| Clarithromycin | 500 mg BID | 300 mg QD | HIV-infected patients (12) | ↑ AUC by 75% | ↓ AUC by 50% | Monitor for rifabutin associated adverse events. Reduce dose or suspend use of rifabutin if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin |
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| Ethambutol | 1200 mg | 300 mg QD × 7 days | Healthy subjects (10) | ND | ↔ | |
| Isoniazid | 300 mg | 300 mg QD × 7 days | Healthy subjects (6) | ND | ↔ | |
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| Methadone | 20 – 100 mg QD | 300 mg QD × 13 days | HIV-infected patients (24) | ND | ↔ | |
| Ethinylestradiol (EE)/ Norethindrone (NE) | 35 mg EE / 1 mg NE × 21 days | 300 mg QD × 10 days | Healthy female subjects (22) | ND | EE: ↓ AUC by 35%, ↓ Cmax by 20% NE: ↓ AUC by 46% |
Patients should be advised to use additional or alternative methods of contraception. |
| Theophylline | 5 mg/kg | 300 mg × 14 days | Healthy subjects (11) | ND | ↔ | |
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Hepatitis C protease inhibitor (boceprevir) |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| AED Coadministered | Dose of AED (mg/day) |
Oxcarbazepine Dose (mg/day) |
Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) | Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400-2000 | 900 | nc |
40% decrease [CI:17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI:12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc up to 40% increase [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc |
18% decrease [CI:13% decrease, 40% decrease] |
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| Known CYP2D6 Poor Metabolizers |
Administer half of usual dose |
| KnownCYP2D6Poor Metabolizersand strongCYP3A4 inhibitors |
Administer a quarter of usualdose |
| StrongCYP2D6 or CYP3A4inhibitors |
Administerhalf of usual dose |
| StrongCYP2D6andCYP3A4 inhibitors |
Administer a quarter of usualdose |
| StrongCYP3A4inducers |
Double usual doseover 1 to 2 weeks |
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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** Results based on ** Results based on *** Non-Nucleoside Reverse Transcriptase Inhibitors |
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| Rifampin* and Rifabutin*
(CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (400 mg q24h)**
(CYP450 Induction) Efavirenz (300 mg q24h)** (CYP450 Induction) |
Significantly Reduced Slight Decrease in |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h)** (CYP450 Induction) Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction) |
Significantly Reduced Reduced |
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin*
(CYP450 Induction) |
Significantly Reduced |
Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John’s Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased |
Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) |
Significantly Increased |
Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
| Other NNRTIs***
(CYP3A4 Inhibition or CYP450 Induction) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness |
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|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
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| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin | Monitor phenytoin level ( |
| Methotrexate | Monitor for methotrexate toxicity ( |
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine ( |
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| Atazanavir/Ritonavir* | ↓ Atazanavir
↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir*
Fosamprenavir/Ritonavir* |
↓ Amprenavir
↑ Nevirapine ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
No dosing adjustments are required when nevirapine is coadministered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* | ↓ Indinavir | The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* | ↓ Lopinavir | Dosing in adult patients:
A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* | ↓ Nelfinavir M8
Metabolite ↓ Nelfinavir C min |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/Ritonavir | The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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||
| Efavirenz*
Delavirdine Etravirine Rilpivirine |
↓ Efavirenz | The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
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| Boceprevir | Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. | Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy. |
| Telaprevir | Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. | Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events. |
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Methadone* |
↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadonemaintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Clarithromycin* Rifabutin* Rifampin* |
↓ Clarithromycin
↑ 14-OH clarithromycin ↑ Rifabutin ↓ Nevirapine |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients coinfected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. | Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* Ketoconazole* Itraconazole |
↑ Nevirapine
↓ Ketoconazole ↓ Itraconazole |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. | Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓Ethinyl estradiol
↓Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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|
|
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
|
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|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Drugs that Affect Renal Function | A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin. | |
|---|---|---|
| Antiarrhythmics | Dofetilide | Concomitant administration with digoxin was associated with a higher rate of torsades de pointes. |
| Sotalol | Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. | |
| Dronedarone | Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin. | |
| Parathyroid Hormone Analog | Teriparatide | Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. |
| Thyroid supplement | Thyroid | Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. |
| Sympathomimetics | Epinephrine Norepinephrine Dopamine |
Can increase the risk of cardiac arrhythmias |
| Neuromuscular Blocking Agents | Succinylcholine | May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin. |
| Supplements | Calcium | If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. |
| Beta-adrenergic blockers and calcium channel blockers | Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block. | |
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|||||
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose Recommendation |
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|
Coadministered Drug |
Risperidone |
AUC |
Cmax |
|
| Enzyme (CYP2D6) Inhibitors |
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| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
|
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
|
Do not exceed 8 mg/day |
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40 mg/day |
4 mg/day |
1.8 |
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| Enzyme (CYP3A/ PgP inducers) Inducers |
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| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
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| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
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| Other Drugs |
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
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metal cations or didanosine |
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time, INR, watch for bleeding ( |
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| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ |
||
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) | Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate |
||
| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
||
| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets is co-administered with oral antidiabetic drugs [see Adverse Reactions ( |
||
| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) | To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin. | ||
| Cyclosporine | Use with caution (transient elevations in serum creatinine) | Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets is co-administered with cyclosporine. | ||
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) | The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anti-coagulant (for example, warfarin). | ||
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels | Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated. | ||
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [ |
||
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised. | ||
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. | ||
| Sildenafil | Use with caution Two-fold increase in exposure | Monitor for sildenafil toxicity [see |
||
| Duloxetine | Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity | ||
| Caffeine/Xanthine Derivatives | Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life | Ciprofloxacin tablets inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. | ||
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| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin tablets should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels |
||
| Probenecid |
Use with caution (interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin tablets serum levels) |
Potentiation of ciprofloxacin tablets toxicity may occur. |
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Hepatitis C protease inhibitor (boceprevir) |
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StrongCYP3A4Inhibitors (e.g.,itraconazole,clarithromycin) or strongCYP2D6inhibitors (e.g.,quinidine,fluoxetine,paroxetine) |
The concomitant use of aripiprazole tablets withstrong CYP3A4 orCYP2D6inhibitorsincreasedthe exposure ofaripiprazole tabletscomparedto the use of aripiprazole tabletsalone
|
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inhibitororCYP2D6inhibitor, reducethearipiprazole tablets dosage
|
| StrongCYP3A4Inducers (e.g.,carbamazepine,rifampin)
|
The concomitant use of aripiprazole tabletsandcarbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone
|
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inducer, consider increasing the aripiprazole tabletsdosage
|
| AntihypertensiveDrugs
|
Duetoitsalphaadrenergicantagonism,aripiprazole tablets hasthepotentialtoenhance the effect of certainantihypertensive agents.
|
Monitor bloodpressureand adjustdoseaccordingly
|
| Benzodiazepines(e.g., lorazepam)
|
Theintensityofsedationwas greaterwith the combination of oral aripiprazole tabletsandlorazepam as comparedtothat observedwith aripiprazole alone.Theorthostatichypotension observed wasgreaterwith the combination as comparedtothatobserved withlorazepamalone
|
Monitorsedation and blood pressure.Adjust dose accordingly.
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
| Known CYP2D6 Poor Metabolizers |
Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors |
Administer a quarter of usual dose |
| Strong CYP2D6 |
Administer half of usual dose |
| Strong CYP2D6 |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers |
Double usual dose over 1 to 2 weeks |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
|
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
|
| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
|
NC or 25% increase
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
|
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|
|
| Thyroid Function | Decreased PBI; increased T 3 uptake |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd) |
| 5 Hydroxyindole acetic acid | False negative with fluorometric test |
| Acetone, Ketone Bodies | False positive FeCl 3 in Gerhardt reaction; red color persists with boiling |
| 17-OH corticosteroids | False reduced values with >4.8 g qd salicylate |
| Vanilmandelic Acid | False reduced values |
| Uric Acid | May increase or decrease depending on dose |
| Prothrombin | Decreased levels; slightly increased prothrombin time |
|
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|
Adenosine |
Theophylline blocks adenosine receptors. |
Higher doses of adenosine may be required to achieve desired effect. |
|
Alcohol |
A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. |
30% increase |
|
Allopurinol |
Decreases theophylline clearance at allopurinol doses ≥600 mg/day. |
25% increase |
|
Aminoglutethimide |
Increases theophylline clearance by induction of microsomal enzyme activity. |
25% decrease |
|
Carbamazepine |
Similar to aminoglutethimide. |
30% decrease |
|
Cimetidine |
Decreases theophylline clearance by inhibiting cytochrome P450 1A2. |
70% increase |
|
Ciprofloxacin |
Similar to cimetidine. |
40% increase |
|
Clarithromycin |
Similar to erythromycin. |
25% increase |
|
Diazepam |
Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. |
Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
|
Disulfiram |
Decreases theophylline clearance by inhibiting hydroxylation and demethylation. |
50% increase |
|
Enoxacin |
Similar to cimetidine. |
300% increase |
|
Ephedrine |
Synergistic CNS effects. |
Increased frequency of nausea, nervousness, and insomnia. |
|
Erythromycin |
Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. |
35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
|
Estrogen |
Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. |
30% increase |
|
Flurazepam |
Similar to diazepam. |
Similar to diazepam. |
|
Fluvoxamine |
Similar to cimetidine. |
Similar to cimetidine. |
|
Halothane |
Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. |
Increased risk of ventricular arrhythmias. |
|
Interferon, human recombinant alpha-A |
Decreases theophylline clearance. |
100% increase |
|
Isoproterenol (IV) |
Increases theophylline clearance. |
20% decrease |
|
Ketamine |
Pharmacologic. |
May lower theophylline seizure threshold |
|
Lithium |
Theophylline increases renal lithium clearance. |
Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
|
Lorazepam |
Similar to diazepam. |
Similar to diazepam. |
|
Methotrexate (MTX) |
Decreases theophylline clearance. |
20% increase after low dose MTX, higher dose MTX may have a greater effect. |
|
Mexiletine |
Similar to disulfiram. |
80% increase |
|
Midazolam |
Similar to diazepam. |
Similar to diazepam. |
|
Moricizine |
Increases theophylline clearance. |
25% decrease |
|
Pancuronium |
Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. |
Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
|
Pentoxifylline |
Decreases theophylline clearance. |
30% increase |
|
Phenobarbital (PB) |
Similar to aminoglutethimide. |
25% decrease after two weeks of concurrent PB. |
|
Phenytoin |
Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. |
Serum theophylline |
|
Propafenone |
Decreases theophylline clearance and pharmacologic interaction. |
40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
|
Propranolol |
Similar to cimetidine and pharmacologic interaction. |
100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
|
Rifampin |
Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. |
20-40% decrease |
| St. John’sWort (Hypericum Perforatum) | Decrease in theophylline plasma concentrations. | Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity. |
|
Sulfinpyrazone |
Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. |
20% decrease |
|
Tacrine |
Similar to cimetidine, also increases renal clearance of theophylline. |
90% increase |
|
Thiabendazole |
Decreases theophylline clearance. |
190% increase |
|
Ticlopidine |
Decreases theophylline clearance. |
60% increase |
|
Troleandomycin |
Similar to erythromycin. |
33-100% increase depending on troleandomycin dose. |
|
Verapamil |
Similar to disulfiram. |
20% increase |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
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|
|
StrongCYP3A4Inhibitors (e.g.,itraconazole,clarithromycin) or strongCYP2D6inhibitors (e.g.,quinidine,fluoxetine,paroxetine) |
The concomitant use of aripiprazole tablets withstrong CYP3A4 orCYP2D6inhibitorsincreasedthe exposure ofaripiprazole tabletscomparedto the use of aripiprazole tabletsalone |
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inhibitororCYP2D6inhibitor, reducethearipiprazole tablets dosage |
| StrongCYP3A4Inducers (e.g.,carbamazepine,rifampin) |
The concomitant use of aripiprazole tabletsandcarbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone |
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inducer, consider increasing the aripiprazole tabletsdosage |
| AntihypertensiveDrugs |
Duetoitsalphaadrenergicantagonism,aripiprazole tablets hasthepotentialtoenhance the effect of certainantihypertensive agents. |
Monitor bloodpressureand adjustdoseaccordingly |
| Benzodiazepines(e.g., lorazepam) |
Theintensityofsedationwas greaterwith the combination of oral aripiprazole tabletsandlorazepam as comparedtothat observedwith aripiprazole alone.Theorthostatichypotension observed wasgreaterwith the combination as comparedtothatobserved withlorazepamalone |
Monitorsedation and blood pressure.Adjust dose accordingly. |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
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Hepatitis C Protease inhibitor (boceprevir) |
|
| ↑Indicates increase. ↓Indicates decrease. |
||
| Drug | Effect | Clinical Comment |
| ganciclovir | ↑didanosine concentration | If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity. |
| methadone | ↓didanosine concentration | If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. |
| nelfinavir | No interaction 1 hour after didanosine | Administer nelfinavir 1 hour after didanosine. |
|
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↑didanosine concentration |
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3 mg twice daily |
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| Drug Class or Drug Name | Clinical Recommendations |
|---|---|
| Digoxin (P-gp substrate) | Measure serum digoxin concentrations before initiating CERDELGA. Reduce digoxin dose by 30% and continue monitoring. |
|
(e.g., phenytoin, colchicine, dabigatran etexilate) |
Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the concomitant drug and titrate to clinical effect. |
|
| CONCOMITANT DRUG | CLINICAL EFFECT(S) |
|---|---|
| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine × 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents, presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| AED Coadministered | AED Concentration | Felbamate Concentration |
|---|---|---|
| Phenytoin | ↑ | ↓ |
| Valproate | ↑ | ↔ |
| Carbamazepine (CBZ) |
↓ ↑ |
↓ |
| Phenobarbital | ↑ | ↓ |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
|
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| |
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1) |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2) |
| Antidiabetic agents | Carefully monitor blood glucose (5.11, 7.3) |
|
|
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|
|
Nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, monoamine oxidase inhibitors, non-selective beta-adrenergic-blocking agents, anabolic hormones (e.g. methandrostenolone), guanethidine, gymnema sylvestre, glucomannan, thioctic acid, and inhibitors of CYP2C9 (e.g. amiodarone, fluconazole, voriconazole, sulfinpyrazone), alcohol. |
|
|
Dose reductions and increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs. |
|
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|
|
Thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, somatostatin analogues (e.g. lanreotide, octreotide), and CYP inducers (e.g. rifampin, phenytoin and St John’s Wort). |
|
|
Dose increases and increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs. |
|
|
|
|
|
beta-blockers, clonidine, guanethidine, and reserpine |
|
|
Increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs. |
|
|
|
| Digoxin Enalapril Iron Metoprolol Warfarin |
|
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|
| Ciprofloxacin Mycophenolate mofetil |
Take at least 2 hours before or 6 hours after sevelamer Take at least 2 hours before sevelamer |
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
These drugs may increase serum thyroxine-binding globulin (TBG) concentration. |
| Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
These drugs may decrease serum TBG concentration. |
| Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations. | |
| Salicylates (> 2 g/day) | Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%. |
| Other drugs: Carbamazepine Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates |
These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters. |
|
|
|
| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
|
|
|
|
|
Adenosine |
Theophylline blocks adenosine receptors. |
Higher doses of adenosine may be required to achieve desired effect. |
|
Alcohol |
A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. |
30% increase |
|
Allopurinol |
Decreases theophylline clearance at allopurinol doses ≥600 mg/day. |
25% increase |
|
Aminoglutethimide |
Increases theophylline clearance by induction of microsomal enzyme activity. |
25% decrease |
|
Carbamazepine |
Similar to aminoglutethimide. |
30% decrease |
|
Cimetidine |
Decreases theophylline clearance by inhibiting cytochrome P450 1A2. |
70% increase |
|
Ciprofloxacin |
Similar to cimetidine. |
40% increase |
|
Clarithromycin |
Similar to erythromycin. |
25% increase |
|
Diazepam |
Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. |
Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
|
Disulfiram |
Decreases theophylline clearance by inhibiting hydroxylation and demethylation. |
50% increase |
|
Enoxacin |
Similar to cimetidine. |
300% increase |
|
Ephedrine |
Synergistic CNS effects. |
Increased frequency of nausea, nervousness, and insomnia. |
|
Erythromycin |
Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. |
35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
|
Estrogen |
Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. |
30% increase |
|
Flurazepam |
Similar to diazepam. |
Similar to diazepam. |
|
Fluvoxamine |
Similar to cimetidine. |
Similar to cimetidine. |
|
Halothane |
Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. |
Increased risk of ventricular arrhythmias. |
|
Interferon, human recombinant alpha-A |
Decreases theophylline clearance. |
100% increase |
|
Isoproterenol (IV) |
Increases theophylline clearance. |
20% decrease |
|
Ketamine |
Pharmacologic. |
May lower theophylline seizure threshold |
|
Lithium |
Theophylline increases renal lithium clearance. |
Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
|
Lorazepam |
Similar to diazepam. |
Similar to diazepam. |
|
Methotrexate (MTX) |
Decreases theophylline clearance. |
20% increase after low dose MTX, higher dose MTX may have a greater effect. |
|
Mexiletine |
Similar to disulfiram. |
80% increase |
|
Midazolam |
Similar to diazepam. |
Similar to diazepam. |
|
Moricizine |
Increases theophylline clearance. |
25% decrease |
|
Pancuronium |
Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. |
Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
|
Pentoxifylline |
Decreases theophylline clearance. |
30% increase |
|
Phenobarbital (PB) |
Similar to aminoglutethimide. |
25% decrease after two weeks of concurrent PB. |
|
Phenytoin |
Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. |
Serum theophylline |
|
Propafenone |
Decreases theophylline clearance and pharmacologic interaction. |
40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
|
Propranolol |
Similar to cimetidine and pharmacologic interaction. |
100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
|
Rifampin |
Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. |
20-40% decrease |
| St. John’sWort (Hypericum Perforatum) | Decrease in theophylline plasma concentrations. | Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity. |
|
Sulfinpyrazone |
Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. |
20% decrease |
|
Tacrine |
Similar to cimetidine, also increases renal clearance of theophylline. |
90% increase |
|
Thiabendazole |
Decreases theophylline clearance. |
190% increase |
|
Ticlopidine |
Decreases theophylline clearance. |
60% increase |
|
Troleandomycin |
Similar to erythromycin. |
33-100% increase depending on troleandomycin dose. |
|
Verapamil |
Similar to disulfiram. |
20% increase |
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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See |
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| * Results based on ** Results based on *** Non-Nucleoside Reverse Transcriptase Inhibitors |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 inducer; P-gp inducer) |
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containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
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(CYP2C9, CYP2C19 and CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition or CYP450 Induction) |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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Monitor patients with concomitant use of oxaprozin tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Concomitant use of oxaprozin tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Oxaprozin tablets are not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of oxaprozin tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of oxaprozin tablets and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of oxaprozin tablets and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate. |
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During concomitant use of oxaprozin tablets and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of oxaprozin tablets and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of oxaprozin tablets and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended. |
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Concomitant use of oxaprozin tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of oxaprozin tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Concomitant use of corticosteroids with oxaprozin tablets may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of oxaprozin tablets with corticosteroids for signs of bleeding [ |
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While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control. |
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During concomitant use of oxaprozin tablets and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy. |
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The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
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Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue
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selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
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Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
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Concomitant use of pimozide and sertraline hydrochloride is contraindicated
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The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
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Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs
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other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
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The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
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Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio
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aspirin, clopidogrel, heparin, warfarin
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Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma
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Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
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warfarin
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Sertraline hydrochloride is a CYP2D6 inhibitor
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Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
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propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
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Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
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Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
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phenytoin, fosphenytoin
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Norepinephrine Dopamine |
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| |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases theophylline clearance at allopurinol doses ≥600 mg/day. | 25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects. | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20 to 40% decrease |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| hiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33 to 100% increase depending on troleandomycin dose. |
| Verapamil | imilar to disulfiram. | 20% increase |
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Hepatitis C protease inhibitor (boceprevir) |
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| AED Co-administered | AED Concentration | Topiramate Concentration |
|---|---|---|
| NC = Less than 10% change in plasma concentration. | ||
| NE = Not Evaluated | ||
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
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Norepinephrine Dopamine |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day. | 25% increase |
| Amino glutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% increase |
| Carbamazepine | Similar to aminoglutethimide | 30% increase |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effect | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3 | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increase risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A |
Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) |
Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60% |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) |
Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increase theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
|
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|
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome. |
|
|
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue |
|
|
selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
|
|
|
|
|
Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias. |
|
|
Concomitant use of pimozide and sertraline hydrochloride is contraindicated |
|
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|
|
|
The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome. |
|
|
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs |
|
|
other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort |
|
|
|
|
|
The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding. |
|
|
Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio |
|
|
aspirin, clopidogrel, heparin, warfarin |
|
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|
|
|
Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma |
|
|
Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted. |
|
|
warfarin |
|
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|
|
|
Sertraline hydrochloride is a CYP2D6 inhibitor |
|
|
Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued. |
|
|
propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine |
|
|
|
|
|
Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations. |
|
|
Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed. |
|
|
phenytoin, fosphenytoin |
| Concomitant Drug Class: Drug Name | Effect on Concentration |
Clinical Comment |
|---|---|---|
|
Antacids |
↓ elvitegravir | Elvitegravir plasma concentrations are lower when STRIBILD is administered simultaneously with antacids. It is recommended to separate STRIBILD and antacid administration by at least 2 hours. |
|
e.g. amiodarone bepridil digoxin disopyramide flecainide systemic lidocaine mexiletine propafenone quinidine |
↑ antiarrhythmics ↑ digoxin |
Concentrations of these antiarrhythmic drugs may be increased when coadministered with STRIBILD. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD. |
|
clarithromycin telithromycin |
↑ clarithromycin ↑ telithromycin ↑ cobicistat |
Concentrations of clarithromycin and/or cobicistat may be altered when clarithromycin is coadministered with STRIBILD. No dose adjustment of clarithromycin is required. The dose of clarithromycin should be reduced by 50%. Concentrations of telithromycin and/or cobicistat may be increased when telithromycin is coadministered with STRIBILD. |
|
warfarin |
Effect on warfarin unknown | Concentrations of warfarin may be affected upon coadministration with STRIBILD. It is recommended that the international normalized ratio (INR) be monitored upon coadministration with STRIBILD. |
|
carbamazepine oxcarbazepine phenobarbital phenytoin |
↑ carbamazepine ↓ elvitegravir ↓ cobicistat |
Coadministration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with STRIBILD may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Alternative anticonvulsants should be considered. |
| clonazepam ethosuximide |
↑ clonazepam ↑ ethosuximide |
Concentrations of clonazepam and ethosuximide may be increased when coadministered with STRIBILD. Clinical monitoring is recommended upon coadministration with STRIBILD. |
|
Selective Serotonin Reuptake Inhibitors (SSRIs) e.g. paroxetine Tricyclic Antidepressants (TCAs) e.g. amitriptyline desipramine imipramine nortriptyline bupropion trazodone |
↑ SSRIs ↑ TCAs ↑ trazodone |
Concentrations of these antidepressant agents may be increased when coadministered with STRIBILD. Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended. |
|
itraconazole ketoconazole voriconazole |
↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑voriconazole |
Concentrations of ketoconazole, itraconazole and voriconazole may increase upon coadministration with STRIBILD. When administering with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day. An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD. |
|
colchicine |
↑ colchicine | STRIBILD is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment. 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
|
rifabutin rifapentine |
↓ elvitegravir ↓ cobicistat |
Coadministration of rifabutin and rifapentine with STRIBILD may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Coadministration of STRIBILD with rifabutin or rifapentine is not recommended. |
|
e.g. metoprolol timolol |
↑ beta-blockers | Concentrations of beta-blockers may be increased when coadministered with STRIBILD. Clinical monitoring is recommended and a dose decrease of the beta blocker may be necessary when these agents are coadministered with STRIBILD. |
|
e.g. amlodipine diltiazem felodipine nicardipine nifedipine verapamil |
↑ calcium channel blockers | Concentrations of calcium channel blockers may be increased when coadministered with STRIBILD. Caution is warranted and clinical monitoring is recommended upon coadministration with STRIBILD. |
|
Systemic: dexamethasone |
↓ elvitegravir ↓ cobicistat |
Systemic dexamethasone, a CYP3A inducer, may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. |
|
Inhaled/Nasal: fluticasone |
↑ fluticasone | Concomitant use of inhaled or nasal fluticasone and STRIBILD may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use. |
|
bosentan |
↑ bosentan |
In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
atorvastatin |
↑ atorvastatin | Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety. |
|
norgestimate/ethinyl estradiol |
↑ norgestimate ↓ ethinyl estradiol |
The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events. Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate has not been studied; therefore, alternative (non-hormonal) methods of contraception can be considered. |
|
e.g. cyclosporine sirolimus tacrolimus |
↑ immuno-suppressants | Concentrations of these immunosuppressant agents may be increased when coadministered with STRIBILD. Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD. |
|
buprenorphine/ naloxone |
↑ buprenorphine ↑ norbuprenorphine ↓ naloxone |
Concentrations of buprenorphine and norbuprenorphine are increased when coadministered with STRIBILD. No dose adjustment of buprenorphine/naloxone is required upon coadministration with STRIBILD. Patients should be closely monitored for sedation and cognitive effects. |
|
salmeterol |
↑ salmeterol | Coadministration of salmeterol and STRIBILD is not recommended. Coadministration of salmeterol with STRIBILD may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
|
e.g. perphenazine risperidone thioridazine |
↑ neuroleptics | A decrease in dose of the neuroleptic may be needed when coadministered with STRIBILD. |
|
sildenafil tadalafil vardenafil |
↑ PDE5 inhibitors | Coadministration with STRIBILD may result in an increase in PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism.
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated with adverse events. |
|
Benzodiazepines: e.g. Parenterally administered midazolam clorazepate diazepam estazolam flurazepam buspirone zolpidem |
↑ sedatives/hypnotics | Concomitant use of parenteral midazolam with STRIBILD may increase plasma concentrations of midazolam. Coadministration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with STRIBILD is contraindicated. With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended. |
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| Phenytoin
|
NC or 25% increase
a
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
b
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
|
|
|
|
| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
|
|
|
|
|
| nafcillin | carbamazepine | bosentan | St. John’s Wort |
| rifampin | oxcarbazepine | octreotide | |
| phenobarbital | orlistat | ||
| phenytoin | sulfinpyrazone | ||
| terbinafine | |||
| ticlopidine | |||
|
|
|
|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
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||
| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). | |
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||
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|
||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | |
|
|
||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | |
|
|
||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | |
|
|
||
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | |
|
|
||
|
|
||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | |
|
|
||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | |
|
|
||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. | |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
|||
|
|
|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
|||
| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Phenytoin |
NCor25%increasea
|
48%decrease |
| Carbamazepine(CBZ) |
NC |
40%decrease |
| CBZepoxideb
|
NC |
NE |
| Valproic acid |
11%decrease |
14%decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NCatTPM dosesupto400 mg/day |
13%decrease |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
| Laboratory Tests | Effect of Salicylates |
|---|---|
| Thyroid Function | Decreased PBI; increased T3 uptake |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd) |
| 5 Hydroxyindole Acetic Acid | False negative with fluorometric test |
| Acetone, Ketone Bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling |
| 17-OH corticosteroids | False reduced values with >4.8 g qd salicylate |
| Vanilmandelic Acid | False reduced values |
| Uric Acid | May increase or decrease depending on dose |
| Prothrombin | Decreased levels; slightly increased prothrombin time |
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ciprofloxacin gentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin |
melphalan amphotericin B ketoconazole |
azapropazon colchicine diclofenac naproxen sulindac |
cimetidine ranitidine tacrolimus fibric acid derivatives (e.g., bezafibrate, fenofibrate) |
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| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – Antagonist: maraviroc |
↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
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| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers: dihydropyridine, felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Long-acting beta-adrenoceptor Agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
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| Dopamine / Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
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| Aminoglutethimide
Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone
Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4, and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. |
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| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
| AED Coadministered | Dose of AED
(mg/day) |
Oxcarbazepine Tablets Dose
(mg/day) |
Influence of Oxcarbazepine Tablets on AED Concentration
(Mean Change, 90% Confidence Interval) |
Influence of AED on MHD Concentration
(Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc
|
40% decrease
[CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase
[CI: 2% increase, 24% increase] |
25% decrease
[CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800
>1200-2400 |
nc
[CI: 12% increase, 60% increase] |
30% decrease
[CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc
|
18% decrease
[CI: 13% decrease, 40% decrease] |
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Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg). |
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Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Celecoxib is not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of celecoxib and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
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During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics. |
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During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ |
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Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see |
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| Multivalent cation-containing products including: antacids, sucralfate, multivitamins |
Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. ( |
| Class IA and Class III antiarrhythmics: |
Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
| Antidiabetic agents |
Carefully monitor blood glucose. ( |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) | The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone
|
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage
|
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) | The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone
|
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage
|
| Antihypertensive Drugs | Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. | Monitor blood pressure and adjust dose accordingly
|
| Benzodiazepines(e.g., lorazepam) | The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone
|
Monitor sedation and blood pressure. Adjust dose accordingly. |
| Concomitant Drug Class: Drug Name | Effect on Concentration |
Clinical Comment |
|---|---|---|
|
Antacids |
↓ elvitegravir | Elvitegravir plasma concentrations are lower when STRIBILD is administered simultaneously with antacids. It is recommended to separate STRIBILD and antacid administration by at least 2 hours. |
|
e.g. amiodarone bepridil digoxin disopyramide flecainide systemic lidocaine mexiletine propafenone quinidine |
↑ antiarrhythmics ↑ digoxin |
Concentrations of these antiarrhythmic drugs may be increased when coadministered with STRIBILD. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD. |
|
clarithromycin telithromycin |
↑ clarithromycin ↑ telithromycin ↑ cobicistat |
Concentrations of clarithromycin and/or cobicistat may be altered when clarithromycin is coadministered with STRIBILD. No dose adjustment of clarithromycin is required. The dose of clarithromycin should be reduced by 50%. Concentrations of telithromycin and/or cobicistat may be increased when telithromycin is coadministered with STRIBILD. |
|
warfarin |
Effect on warfarin unknown | Concentrations of warfarin may be affected upon coadministration with STRIBILD. It is recommended that the international normalized ratio (INR) be monitored upon coadministration with STRIBILD. |
|
carbamazepine oxcarbazepine phenobarbital phenytoin |
↑ carbamazepine ↓ elvitegravir ↓ cobicistat |
Coadministration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with STRIBILD may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Alternative anticonvulsants should be considered. |
| clonazepam ethosuximide |
↑ clonazepam ↑ ethosuximide |
Concentrations of clonazepam and ethosuximide may be increased when coadministered with STRIBILD. Clinical monitoring is recommended upon coadministration with STRIBILD. |
|
Selective Serotonin Reuptake Inhibitors (SSRIs) e.g. paroxetine Tricyclic Antidepressants (TCAs) e.g. amitriptyline desipramine imipramine nortriptyline buproprion trazodone |
↑ SSRIs ↑ TCAs ↑ trazodone |
Concentrations of these antidepressant agents may be increased when coadministered with STRIBILD. Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended. |
|
itraconazole ketoconazole voriconazole |
↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑voriconazole |
Concentrations of ketoconazole, itraconazole and voriconazole may increase upon coadministration with STRIBILD. When administering with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day. An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD. |
|
colchicine |
↑ colchicine | STRIBILD is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment. 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
|
rifabutin rifapentine |
↓ elvitegravir ↓ cobicistat |
Coadministration of rifabutin and rifapentine with STRIBILD may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Coadministration of STRIBILD with rifabutin or rifapentine is not recommended. |
|
e.g. metoprolol timolol |
↑ beta-blockers | Concentrations of beta-blockers may be increased when coadministered with STRIBILD. Clinical monitoring is recommended and a dose decrease of the beta blocker may be necessary when these agents are coadministered with STRIBILD. |
|
e.g. amlodipine diltiazem felodipine nicardipine nifedipine verapamil |
↑ calcium channel blockers | Concentrations of calcium channel blockers may be increased when coadministered with STRIBILD. Caution is warranted and clinical monitoring is recommended upon coadministration with STRIBILD. |
|
Systemic: dexamethasone |
↓ elvitegravir ↓ cobicistat |
Systemic dexamethasone, a CYP3A inducer, may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. |
|
Inhaled/Nasal: fluticasone |
↑ fluticasone | Concomitant use of inhaled or nasal fluticasone and STRIBILD may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use. |
|
bosentan |
↑ bosentan |
In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
atorvastatin |
↑ atorvastatin | Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety. |
|
norgestimate/ethinyl estradiol |
↑ norgestimate ↓ ethinyl estradiol |
The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events. Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate has not been studied; therefore, alternative (non-hormonal) methods of contraception can be considered. |
|
e.g. cyclosporine sirolimus tacrolimus |
↑ immuno-suppressants | Concentrations of these immunosuppressant agents may be increased when coadministered with STRIBILD. Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD. |
|
buprenorphine/ naloxone |
↑ buprenorphine ↑ norbuprenorphine ↓ naloxone |
Concentrations of buprenorphine and norbuprenorphine are increased when coadministered with STRIBILD. No dose adjustment of buprenorphine/naloxone is required upon coadministration with STRIBILD. Patients should be closely monitored for sedation and cognitive effects. |
|
salmeterol |
↑ salmeterol | Coadministration of salmeterol and STRIBILD is not recommended. Coadministration of salmeterol with STRIBILD may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
|
e.g. perphenazine risperidone thioridazine |
↑ neuroleptics | A decrease in dose of the neuroleptic may be needed when coadministered with STRIBILD. |
|
sildenafil tadalafil vardenafil |
↑ PDE5 inhibitors | Coadministration with STRIBILD may result in an increase in PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism.
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated with adverse events. |
|
Benzodiazepines: e.g. Parenterally administered midazolam clorazepate diazepam estazolam flurazepam buspirone zolpidem |
↑ sedatives/hypnotics | Concomitant use of parenteral midazolam with STRIBILD may increase plasma concentrations of midazolam. Coadministration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with STRIBILD is contraindicated. With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended. |
|
|
Effect on Concentration of Delavirdine or Concomitant Drug | Clinical Comment |
| HIV-Antiviral Agents | ||
| Amprenavir | ↑Amprenavir | Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established. |
| Didanosinea |
|
Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least 1 hour. |
| Indinavira | ↑Indinavir | A dose reduction of indinavir to 600 mg 3 times daily should be considered when RESCRIPTOR and indinavir are coadministered. |
| Lopinavir/Ritonavir |
|
Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established. |
| Nelfinavira |
|
Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established. (See CLINICAL PHARMACOLOGY: Tables 1 and 2.) |
| Ritonavir | ↑Ritonavir | Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established. |
|
|
|
A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered (see CLINICAL PHARMACOLOGY: Table 1). Appropriate doses with respect to safety, efficacy, and pharmacokinetics have not been established. |
| Other Agents | ||
|
|
↓Delavirdine | Doses of an antacid and RESCRIPTOR should be separated by at least 1 hour, because the absorption of delavirdine is reduced when coadministered with antacids. |
|
|
↓Delavirdine | These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended. |
|
|
↓Delavirdine | These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended. |
|
|
↑Amphetamines |
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|
↑Trazodone | Concomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazadone should be considered. |
|
|
↑Antiarrhythmics | Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias. |
| Amiodarone,lidocaine (systemic), quinidine, flecainide, propafenone | Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR. | |
|
|
↑Warfarin | It is recommended that INR (international normalized ratio) be monitored. |
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|
↑Calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
|
|
↓Delavirdine | Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly. |
|
|
↑Sildenafil | Sildenafil should not exceed a maximum single dose of 25 mg in a 48-hour period. |
|
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|
Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR. |
|
|
↑Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR. |
|
|
↑Fluticasone | Concomitant use of fluticasone propionate and RESCRIPTOR may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
|
|
↑Methadone | Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR. |
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↑Ethinyl estradiol | Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown. |
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| Theophylline |
Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents |
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin |
Monitor phenytoin level ( |
| Methotrexate |
Monitor for methotrexate toxicity ( |
| Cyclosporine |
May increase serum creatinine. Monitor serum creatinine ( |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide
|
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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|
|
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
|
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
|
||
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|
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 | ||
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|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 | ||
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|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
Coadministered |
(mg/day) |
(mg/day) |
Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400-2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
| Lamotrigine | 200 | 1200 | nc1 | nc1 |
|
|
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|
|
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
|
|---|---|---|
|
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|
|
|
|
|
|
|
| AED Coadministered |
AED Concentration |
Topiramate Concentration |
|
|
||
| Phenytoin |
NC or 25% increasea |
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb |
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
|
|
|
| Anticoagulants
|
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
|
| Antiplatelet Agents
|
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
|
| Nonsteroidal Anti-Inflammatory Agents
|
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
|
| Serotonin Reuptake Inhibitors
|
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone
|
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Etravirine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↑ = increase, ↓ = decrease, ↔ = no change | ||
|
|
||
| efavirenz nevirapine |
↓ etravirine | Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered. |
| delavirdine | ↑ etravirine | Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered. |
| rilpivirine | ↓ rilpivirine ↔ etravirine |
Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and rilpivirine should not be coadministered. |
|
|
||
| atazanavir (without ritonavir) |
↓ atazanavir | Concomitant use of INTELENCE® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir. |
| atazanavir/ritonavir |
↓ atazanavir ↑ etravirine |
Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered. |
| darunavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments. |
| fosamprenavir (without ritonavir) |
↑ amprenavir | Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir. |
| fosamprenavir/ritonavir |
↑ amprenavir | Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered. |
| indinavir (without ritonavir) |
↓ indinavir | Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir. |
| lopinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments. |
| nelfinavir (without ritonavir) |
↑ nelfinavir | Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir. |
| ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg twice daily should not be co-administered. |
| saquinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments. |
| tipranavir/ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered. |
|
|
||
| maraviroc |
↔ etravirine ↓ maraviroc |
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE® is needed. |
| maraviroc/darunavir/ritonavir |
↔ etravirine ↑ maraviroc |
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE® is needed. |
|
|
||
|
digoxin |
↔ etravirine ↑ digoxin |
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. |
| amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine |
↓ antiarrhythmics | Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available. |
|
warfarin |
↑ anticoagulants | Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®. |
|
carbamazepine, phenobarbital, phenytoin |
↓ etravirine | Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
|
fluconazole voriconazole |
↑ etravirine ↔ fluconazole ↑ voriconazole |
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed. |
| Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed. | ||
|
itraconazole, ketoconazole, posaconazole |
↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole |
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs. |
|
clarithromycin |
↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin |
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against |
|
rifampin, rifapentine |
↓ etravirine | Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
|
rifabutin |
↓ etravirine ↓ rifabutin ↓ 25- |
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure. |
|
diazepam |
↑ diazepam | Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. |
|
dexamethasone (systemic) |
↓ etravirine | Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use. |
|
St. John's wort ( |
↓ etravirine | Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered. |
|
atorvastatin fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin |
↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↑ pitavastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin |
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary. |
|
cyclosporine, sirolimus, tacrolimus |
↓ immunosuppressant | INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected. |
|
buprenorphine, buprenorphine/naloxone methadone |
↔ etravirine ↓ buprenorphine ↔ norbuprenorphine ↔ methadone |
INTELENCE® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
|
sildenafil tadalafil, vardenafil |
↓ sildenafil ↓ N-desmethyl-sildenafil |
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect. |
|
clopidogrel |
↓ clopidogrel (active) metabolite | Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered. |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
|
|
|
|
|
Decreased exposure of omeprazole when used concomitantly with strong inducers |
|
|
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole Ritonavir-containing products: see prescribing information for specific drugs. |
|
|
|
|
|
Increased exposure of omeprazole |
|
|
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole. |
|
|
||
| Concomitant Drug
|
Effect on Concentration of
Lamotrigine or Concomitant Drug |
Clinical Comment
|
| Estrogen-containing oral
contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine
↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%.
Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide
|
↓ lamotrigine
? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine
concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 40%.
|
| Phenytoin (PHT)
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 40%.
|
| Rifampin
|
↓ lamotrigine
|
Decreased lamotrigine AUC approximately 40%.
|
| Valproate
|
↑ lamotrigine
? valproate |
Increased lamotrigine concentrations slightly
more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
|
|
The concomitant
use of OXYCONTIN and CYP3A4 inhibitors can increase the plasma concentration
of oxycodone, resulting in increased or prolonged opioid effects.
These effects could be more pronounced with concomitant use of OXYCONTIN
and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is
added after a stable dose of OXYCONTIN is achieved After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease |
|
|
If concomitant
use is necessary, consider dosage reduction of OXYCONTIN until stable
drug effects are achieved. Monitor patients for respiratory depression
and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the OXYCONTIN dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
|
|
Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
|
|
|
|
|
The concomitant
use of OXYCONTIN and CYP3A4 inducers can decrease the plasma concentration
of oxycodone After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase |
|
|
If concomitant
use is necessary, consider increasing the OXYCONTIN dosage until stable
drug effects are achieved. Monitor for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider OXYCONTIN dosage reduction
and monitor for signs of respiratory depression. Rifampin, carbamazepine, phenytoin |
|
|
|
|
|
Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
|
|
Reserve concomitant
prescribing of these drugs for use in patients for whom alternative
treatment options are inadequate. Limit dosages and durations to the
minimum required. Follow patients closely for signs of respiratory
depression and sedation |
|
|
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
|
|
|
|
|
The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
|
|
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OXYCONTIN if serotonin syndrome is suspected. |
|
|
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
|
|
|
|
|
MAOI interactions
with opioids may manifest as serotonin syndrome or opioid toxicity
(e.g., respiratory depression, coma) |
|
|
The use of OXYCONTIN is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
|
|
phenelzine, tranylcypromine, linezolid |
|
|
|
|
|
May reduce the analgesic effect of OXYCONTIN and/or precipitate withdrawal symptoms. |
|
|
Avoid concomitant use. |
|
|
butorphanol, nalbuphine, pentazocine, buprenorphine |
|
|
|
|
|
Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
|
|
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OXYCONTIN and/or the muscle relaxant as necessary. |
|
|
|
|
|
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
|
|
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
|
|
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|
|
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
|
|
Monitor patients for signs of urinary retention or reduced gastric motility when OXYCONTIN is used concomitantly with anticholinergic drugs. |
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| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
|
|
|
|
|
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
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|
|
Glucocorticoids Octreotide |
|
|
|
|
|
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|
|
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
|
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|
|
Iodide (including iodine-containing Radiographic contrast agents) |
|
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|
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
|
|
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|
|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
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|
|
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
|
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|
|
|
|
|
Hydantoins Phenobarbital Rifampin |
|
|
|
|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
|
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
|
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
|
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
|
|
|
|
|
- Interferon-α - Interleukin-2 |
|
|
- Somatrem - Somatropin |
|
|
|
|
|
- (e.g., Theophylline) |
|
|
|
|
|
|
|
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
|
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| NA – Not available/reported | |||
|
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|||
|
Concentration Increase |
Increase |
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|
diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole, |
|
||
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|||
|
cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine |
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were studied but reported no significant changes on digoxin exposure. |
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(increased and decreased) |
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Five-fold increase in duloxetine exposure |
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of serum half-life |
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| Interacting Drug | Interaction |
|---|---|
| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin | Monitor phenytoin level ( |
| Methotrexate | Monitor for methotrexate toxicity ( |
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine | Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( |
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
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fibrates, gemfibrozil |
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digoxin |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine |
Decreased lamotrigine levels approximately 50%. |
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↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
|
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? CBZ epoxide |
May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40% |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40% |
| Valproate |
↑ lamotrigine |
Increased lamotrigine concentrations slightly more than 2-fold. |
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? valproate |
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Sulfonylureas | Hypoglycemia potentiated. | ||
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. | ||
| Oral Anticoagulants | Increased bleeding. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. | ||
| Acidifying Agents | Increases plasma salicylate levels. | ||
| Alkanizing Agents | Decreased plasma salicylate levels. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. | ||
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. | ||
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. | ||
| The following alterations of laboratory tests have been reported during salicylate therapy: | |||
| LABORATORY TESTS | EFFECT OF SALICYLATES | ||
| Thyroid Function | Decreased PBI; increased t3 uptake. | ||
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). | ||
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. | ||
| Acetone ketone bodies | False positive FeCI3 in Gerhardt reaction; red color persists with boiling. | ||
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. | ||
| Vanilmandelic acid | False reduced values. | ||
| Uric Acid | May increase or decrease depending on dose. | ||
| Prothrombin | Decreased levels; slightly increased prothrombin time. | ||
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
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| albuterol, systemic and inhaled | hydrocortisone | nizatidine |
| amoxicillin | isoflurane | norfloxacin |
| ampicillin, with or without sulbactam | isoniazid | ofloxacin |
| atenolol | isradipine | omeprazole |
| azithromycin | influenza vaccine | prednisone, prednisolone |
| caffeine, dietary ingestion | ketoconazole | ranitidine |
| cefaclor | lomefloxacin | rifabutin |
| co-trimoxazole | mebendazole | roxithromycin |
| (trimethoprim and sulfamethoxazole) diltiazem | medroxyprogesterone | sorbitol |
| dirithromycin | methylprednisolone | (purgative doses do not inhibit theophylline absorption) |
| enflurane | metronidazole | sucralfate |
| famotidine | metoprolol | terbutaline, systemic |
| felodipine | nadolol | terfenadine |
| finasteride | nifedipine | tetracycline tocainide |
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| Clinical Impact: | Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. | |
| Intervention: |
Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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| Clinical Impact: |
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
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| Intervention: |
Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
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| Clinical Impact: | NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. | |
| Intervention: |
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [
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| Clinical Impact: |
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [
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| Intervention: |
Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [
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| Clinical Impact: | The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. | |
| Intervention: | During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. | |
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| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. | |
| Intervention: | During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. | |
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| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). | |
| Intervention: | During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity. | |
| Intervention: | During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. | |
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| Clinical Impact: |
Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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| Intervention: | The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). | |
| Intervention: | During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. | |
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| Clinical Impact: | When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. | |
| Intervention: | During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. | |
| *Refer to |
|||
| albuterol, systemic and inhaled | hydrocortisone | nizatidine | |
| amoxicillin | isoflurane | norfloxacin | |
| ampicillin, with or without sulbactam | isoniazid | ofloxacin | |
| atenolol | isradipine | omeprazole | |
| azithromycin | influenza vaccine | prednisone, prednisolone | |
| caffeine, dietary ingestion | ketoconazole | ranitidine | |
| cefaclor | lomefloxacin | rifabutin | |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | mebendazole | roxithromycin | |
| diltiazem | medroxyprogesterone | sorbitol (purgative doses do not inhibit | |
| dirithromycin | methylprednisolone | theophylline absorption) | |
| enflurane | metronidazole | sucralfate | |
| famotidine | metoprolol | terbutaline, systemic | |
| felodipine | nadolol | terfenadine | |
| finasteride | nifedipine | tetracycline | |
| tocainide | |||
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Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
|
Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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|
|
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
|
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|
Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [
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The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib capsules have no effect on methotrexate pharmacokinetics. |
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During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
|
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During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [
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Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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Decreased exposure of omeprazole when used concomitantly with strong inducers |
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St. John’s Wort, rifampin: Avoid concomitant use with omeprazole Ritonavir-containing products: see prescribing information for specific drugs. |
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Increased exposure of omeprazole |
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Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole. |
| LABORATORY TESTS | EFFECT OF SALICYLATES |
| Thyroid Function | Decreased PBI; increased T3 uptake. |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). |
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. |
| Acetone, ketone bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling. |
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. |
| Vanilmandelic acid | False reduced values. |
| Uric acid | May increase or decrease depending on dose. |
| Prothrombin | Decreased levels; slightly increased prothrombin time. |
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|
Concomitant Drug |
|
| Zidovudine |
↓ Ganciclovir ↑ Zidovudine |
Zidovudine and valganciclovir tablets each have the potential to cause neutropenia and anemia |
| Probenicid |
↑ Ganciclovir |
Patients taking probenicid and valganciclovir tablets should be monitored for evidence of ganciclovir toxicity |
| Mycophenolate Mofetil (MMF) |
↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) |
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase |
| Didanosine |
↓ Ganciclovir ↑ Didanosine |
Patients should be closely monitored for didanosine toxicity |
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
|
| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
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| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents,presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
| Drug/Drug Class (Mechanism of Interaction by Voriconazole) |
Drug Plasma Exposure (Cmax and AUCτ) |
Recommendations for Drug Dosage Adjustment/Comments |
|---|---|---|
| Sirolimus (CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (400 mg q24h) (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (300 mg q24h) (CYP3A4 Inhibition) |
Slight Increase in AUCτ | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ |
|
| Low-dose Ritonavir (100 mg q12h) |
Slight Decrease in Ritonavir Cmax and AUCτ | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
|
| Cyclosporine (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) |
Increased | Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary |
| Oxycodone (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary |
| NSAIDs (CYP2C9 Inhibition) |
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed |
| Tacrolimus (CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin (CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole (CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment for indinavir when coadministered with VFEND |
|
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors | |
| Other NNRTIs (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
| Everolimus (CYP3A4 Inhibition) |
Not Studied |
Concomitant administration of voriconazole and everolimus is not recommended. |
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| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| |
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| AED Coadministered | Dose of AED (mg/day) | Oxcarbazepine Dose (mg/day) | Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) | Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine |
400 to 2,000 |
900 |
nc |
40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital |
100 to 150 |
600 to 1,800 |
14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin |
250 to 500 |
600 to 1,800 >1,200 to 2,400 |
nc up to 40% increase |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid |
400 to 2,800 |
600 to 1,800 |
nc |
18% decrease [CI: 13% decrease, 40% decrease] |
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In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg). |
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Celecoxib is not a substitute for low dose aspirin for cardiovascular protection. |
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Celecoxib has no effect on methotrexate pharmacokinetics. |
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NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level (
|
| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (
|
| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (
|
| Phenytoin | Monitor phenytoin level (
|
| Methotrexate | Monitor for methotrexate toxicity (
|
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine (
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Decreased Ciprofloxacin Tablets, USP absorption. Take 2 hours before or 6 hours after Ciprofloxacin Tablets, USP (
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The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
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Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. |
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Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range. |
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Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted |
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A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate. |
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Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy |
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Increased exposure of citalopram leading to an increased risk of QT prolongation |
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Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. |
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Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) |
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Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. |
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Potential for increased exposure of phenytoin. |
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Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin. |
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Increased exposure of diazepam |
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Monitor patients for increased sedation and reduce the dose of diazepam as needed. |
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Potential for increased exposure of digoxin |
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Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information. |
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Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. |
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Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF See the prescribing information for other drugs dependent on gastric pH for absorption. |
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Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. |
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See See |
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Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 |
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Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. |
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Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors |
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Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. |
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Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. |
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Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline |
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There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. |
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An alternative confirmatory method should be considered to verify positive results. |
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There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram). |
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Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole. |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( |
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Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology ( |
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During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
| *Change relative to reference |
|||||
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose Recommendation |
||
| Coadministered Drug |
Risperidone |
AUC |
Cmax |
||
| Enzyme (CYP2D6) inhibitors |
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|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day |
4 mg/day |
1.6 |
- |
||
| 40 mg/day |
4 mg/day |
1.8 |
- |
||
| Enzyme (CYP3A/ PgP inducers) Inducers |
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|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) inhibitors |
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| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not Needed |
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| Carbamazepine | 400-2000 | 900 | nc |
|
| Phenobarbital | 100-150 | 600-1800 |
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| Phenytoin | 250-500 |
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| Valproic acid | 400-2800 | 600-1800 | nc |
|
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Co-administered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) | Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6)Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | Re-evaluate dosing. Do not exceed 8 mg/day | |
| Enzyme (CYP3A/PgP inducers)Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents, presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
| Name of the Concomitant Drug | Change in the Concentration of Ganciclovir or Concomitant Drug | Clinical Comment |
|---|---|---|
| Zidovudine | ↓ Ganciclovir ↑ Zidovudine |
|
| Probenecid | ↑ Ganciclovir |
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| Mycophenolate Mofetil (MMF) | ↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) |
|
| Didanosine | ↓ Ganciclovir ↑ Didanosine |
Patients should be closely monitored for didanosine toxicity |
| Drug/Drug Class (Mechanism of Interaction by the Drug) |
Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg q12h) |
Recommendations for Voriconazole Dosage Adjustment/Comments |
|---|---|---|
| Rifampin (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (400 mg q24h) (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (300 mg q24h) (CYP450 Induction) |
Slight Decrease in AUC |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
Significantly Reduced |
|
| Low-dose Ritonavir (100 mg q12h) |
Reduced | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John's Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole |
Significantly Increased | Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir |
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Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors | |
| Other NNRTIs (CYP3A4 Inhibition or CYP450 Induction) |
|
Frequent monitoring for adverse events and toxicity related to voriconazole |
| A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Careful assessment of voriconazole effectiveness |
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| CONCOMITANT DRUG | CLINICAL EFFECT(S) |
|---|---|
| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents, presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
| Opioids | Cross-tolerance and mutual potentiation |
| Naltrexone | Oral THC effects were enhanced by opioid receptor blockade. |
| Alcohol | Increase in the positive subjective mood effects of smoked marijuana |
| NA – Not available/reported | |||
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| Concentration Increase |
Increase |
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| diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole, |
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| cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine |
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| were studied but reported no significant changes on digoxin exposure. |
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Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. |
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Dose reductions and increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs. |
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Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones |
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Dose increases and increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs. |
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Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. |
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Dose adjustment and increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs. |
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beta-blockers, clonidine, guanethidine, and reserpine |
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Increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs. |
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The concomitant
use of OXYCONTIN and CYP3A4 inhibitors can increase the plasma concentration
of oxycodone, resulting in increased or prolonged opioid effects.
These effects could be more pronounced with concomitant use of OXYCONTIN
and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is
added after a stable dose of OXYCONTIN is achieved After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease |
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If concomitant
use is necessary, consider dosage reduction of OXYCONTIN until stable
drug effects are achieved. Monitor patients for respiratory depression
and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the OXYCONTIN dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
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The concomitant
use of OXYCONTIN and CYP3A4 inducers can decrease the plasma concentration
of oxycodone After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase |
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If concomitant
use is necessary, consider increasing the OXYCONTIN dosage until stable
drug effects are achieved. Monitor for signs of opioid withdrawal.
If a CYP3A4 inducer is discontinued, consider OXYCONTIN dosage reduction
and monitor for signs of respiratory depression. Rifampin, carbamazepine, phenytoin |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant
prescribing of these drugs for use in patients for whom alternative
treatment options are inadequate. Limit dosages and durations to the
minimum required. Follow patients closely for signs of respiratory
depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OXYCONTIN if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions
with opioids may manifest as serotonin syndrome or opioid toxicity
(e.g., respiratory depression, coma) |
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The use of OXYCONTIN is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of OXYCONTIN and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OXYCONTIN and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when OXYCONTIN is used concomitantly with anticholinergic drugs. |
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The concomitant use of beta-blockers and Glucagon for Injection may increase the risk of a temporary increase in heart rate and blood pressure. |
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The increase in blood pressure and heart rate may require therapy in patients with coronary artery disease. |
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Insulin reacts antagonistically towards glucagon. |
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Monitor blood glucose when Glucagon for Injection is used as a diagnostic aid in diabetes patients. |
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The concomitant use of indomethacin and Glucagon for Injection may lead to hypoglycemia. |
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Monitor blood glucose levels during glucagon treatment of patients taking indomethacin. |
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The concomitant use of anticholinergic drugs and Glucagon for Injection increase the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility. |
|
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Concomitant use is not recommended. |
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Glucagon may increase the anticoagulant effect of warfarin. |
|
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Monitor patients for unusual bruising or bleeding, as adjustments in warfarin dosage may be required. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (
|
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
|
| Antidiabetic agents | Carefully monitor blood glucose (
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| Known CYP2D6 Poor Metabolizers |
Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors |
Administer a quarter of usual dose |
| Strong CYP2D6 |
Administer half of usual dose |
| Strong CYP2D6 |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers |
Double usual dose over 1 to 2 weeks |
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| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| ↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
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150 mcg levonorgestrel |
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
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? carbamazepine epoxide |
May increase carbamazepine epoxide levels. |
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? valproate |
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
|
(Mechanism of Interaction by Voriconazole) |
(Cmax and AUCτ) |
|
|---|---|---|
| Sirolimus*
(CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin*
(CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (400 mg q24h)†
(CYP450 Induction) Efavirenz (300 mg q24h)† (CYP450 Induction) |
Significantly Increased Slight Increase in AUCτ |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High dose Ritonavir (400 mg q12h)†(CYP3A4 Inhibition) Low dose Ritonavir (100 mg q12h)† |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ Slight Decrease in Ritonavir Cmax and AUCτ |
Cmax and AUCτ Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
|
| Cyclosporine*
(CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax
|
When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone‡ (CYP3A4 Inhibition) |
Increased |
Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) |
Increased |
Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| Alfentanil (CYP3A4 Inhibition) |
Significantly Increased |
Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ |
| Oxycodone (CYP3A4 Inhibition) |
Significantly Increased |
Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| NSAIDs |
Increased |
Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ |
| Tacrolimus*
(CYP3A4 Inhibition) |
Significantly Increased |
When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin*
(CYP2C9 Inhibition) |
Significantly Increased |
Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)†
|
Increased |
Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin*
(CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased |
Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole*
(CYP2C19/3A4 Inhibition) |
Significantly Increased |
When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
No dosage adjustment for indinavir when coadministered with voriconazole Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors |
| Other NNRTIs (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
| Everolimus (CYP3A4 Inhibition) |
Not Studied |
Concomitant administration of voriconazole and everolimus is not recommended. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Interacting Drug | Interaction |
|---|---|
| Drugs known to prolong QT interval (e.g., Class IA and Class III anti-arrhythmic agents). | Quinine Sulfate Capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use ( |
| Other antimalarials (e.g., halofantrine, mefloquine). | ECG abnormalities including QT prolongation. Avoid concomitant use ( |
| CYP3A4 inducers or inhibitors | Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( |
| CYP3A4 and CYP2D6 substrates | Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( |
| Digoxin | Increased digoxin plasma concentration ( |
| NA – Not available/reported | |||
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
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Concentration of Lamotrigine or Concomitant Drug |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
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Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide |
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Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
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Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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See |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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Hepatitis C protease inhibitor (boceprevir) |
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• Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Naproxen delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection. |
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• In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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• During concomitant use of naproxen delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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| AED co-administered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazaepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400mg/day | 13% decrease |
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
|
| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
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Hepatitis C Protease inhibitor (boceprevir) |
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Coadministered Drug | Dose of Coadministered Drug | Dose of Azithromycin | n | Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 | |
| Mean Cmax | Mean AUC | ||||
| Atorvastatin | 10 mg/day x 8 days | 500 mg/day PO on days 6 to 8 | 12 | 0.83 (0.63 to 1.08) | 1.01 (0.81 to 1.25) |
| Carbamazepine | 200 mg/day x 2 days, then 200 mg BID x 18 days | 500 mg/day PO for days 16 to 18 | 7 | 0.97 (0.88 to 1.06) | 0.96 (0.88 to 1.06) |
| Cetirizine | 20 mg/day x 11 days | 500 mg PO on day 7, then 250 mg/day on days 8 to 11 | 14 | 1.03 (0.93 to 1.14) | 1.02 (0.92 to 1.13) |
| Didanosine | 200 mg PO BID x 21 days | 1,200 mg/day PO on days 8 to 21 | 6 | 1.44 (0.85 to 2.43) | 1.14 (0.83 to 1.57) |
| Efavirenz | 400 mg/day x 7 days | 600 mg PO on day 7 | 14 | 1.04* | 0.95* |
| Fluconazole | 200 mg PO single dose | 1,200 mg PO single dose | 18 | 1.04 (0.98 to 1.11) | 1.01 (0.97 to 1.05) |
| Indinavir | 800 mg TID x 5 days | 1,200 mg PO on day 5 | 18 | 0.96 (0.86 to 1.08) | 0.90 (0.81 to 1.00) |
| Midazolam | 15 mg PO on day 3 | 500 mg/day PO x 3 days | 12 | 1.27 (0.89 to 1.81) | 1.26 (1.01 to 1.56) |
| Nelfinavir | 750 mg TID x 11 days | 1,200 mg PO on day 9 | 14 | 0.90 (0.81 to 1.01) | 0.85 (0.78 to 0.93) |
| Rifabutin | 300 mg/day x 10 days | 500 mg PO on day 1, then 250 mg/day on days 2 to 10 | 6 | See footnote below | NA |
| Sildenafil | 100 mg on days 1 and 4 | 500 mg/day PO x 3 days | 12 | 1.16 (0.86 to 1.57) | 0.92 (0.75 to 1.12) |
| Theophylline | 4 mg/kg IV on days 1, 11, 25 | 500 mg PO on day 7, 250 mg/day on days 8 to 11 | 10 | 1.19 (1.02 to 1.40) | 1.02 (0.86 to 1.22) |
| Theophylline | 300 mg PO BID x 15 days | 500 mg PO on day 6, then 250 mg/day on days 7 to 10 | 8 | 1.09 (0.92 to 1.29) | 1.08 (0.89 to 1.31) |
| Triazolam | 0.125 mg on day 2 | 500 mg PO on day 1, then 250 mg/day on day 2 | 12 | 1.06* | 1.02* |
| Trimethoprim/ Sulfamethoxazole | 160 mg/800 mg/day PO x 7 days | 1,200 mg PO on day 7 | 12 | 0.85 (0.75 to 0.97)/0.90 (0.78 to 1.03) | 0.87 (0.80 to 0.95)/0.96 (0.88 to 1.03) |
| Zidovudine | 500 mg/day PO x 21 days | 600 mg/day PO x 14 days | 5 | 1.12 (0.42 to 3.02) | 0.94 (0.52 to 1.70) |
| Zidovudine | 500 mg/day PO x 21 days | 1,200 mg/day PO x 14 days | 4 | 1.31 (0.43 to 3.97) | 1.30 (0.69 to 2.43) |
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Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole. |
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Dose adjustment of ZEMPLAR capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor. |
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Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol. |
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Recommend to take ZEMPLAR capsules at least 1 hour |
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Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol. |
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Recommend to take ZEMPLAR capsules at least 1 hour |
| Classes of Drugs | |||
| 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials
|
Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†
|
Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†
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ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
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(Plasma Exposure Likely to be Increased and Prolonged) |
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Prolong QT Interval |
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Glucose-lowering effect potentiated |
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Altered serum levels of phenytoin (increased and decreased) |
decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin. |
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(transient elevations in serum creatinine) |
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(Increase in anticoagulant effect) |
and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
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Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
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and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin |
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acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
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Two-fold increase in exposure |
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Five-fold increase in duloxetine exposure |
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Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
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(interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
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| Specific Drugs Reported | |||
| also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
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| alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone |
cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate |
6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone |
propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
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|
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||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio
|
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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| DRUG INTERACTIONS |
|
|
|
|
| Known CYP2D6 Poor Metabolizers |
Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors |
Administer a quarter of usual dose |
| Strong CYP2D6 or CYP3A4 inhibitors |
Administer half of usual dose |
| Strong CYP2D6 and CYP3A4 inhibitors |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers |
Double usual dose over 1 to 2 weeks |
|
|
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||
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|
|||
| Dopamine/Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone
Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
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|
|
Hepatitis C protease inhibitor (boceprevir) |
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| |
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| |
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| |
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| |
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| |
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| |
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| |
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| |
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| |
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||
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|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Drug Class: Drug Name | Clinical Comment |
|
|
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs. |
|
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
|
|
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs or other coadministered antiviral agents. |
|
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
|
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
|
( |
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs. |
|
|
Potential for serious reactions such as risk of myopathy including rhabdomyolysis. |
|
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
|
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. |
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| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (
|
|
|
|
|
|
|
Avoid atorvastatin
|
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily
|
| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
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• Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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• Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see WARNINGS AND PRECAUTIONS ( |
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• Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see WARNINGS AND PRECAUTIONS ( |
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Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS ( |
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• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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• During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see WARNINGS AND PRECAUTIONS ( |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see WARNINGS AND PRECAUTIONS ( |
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The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of celecoxib and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib capsules has no effect on methotrexate pharmacokinetics. |
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During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see WARNINGS AND PRECAUTIONS ( |
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The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see CLINICAL PHARMACOLOGY ( |
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(e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see CLINICAL PHARMACOLOGY ( |
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Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see WARNINGS AND PRECAUTIONS ( |
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The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine
|
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
|
| Warfarin
|
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
|
| Antidiabetic agents
|
Carefully monitor blood glucose (
|
| albuterol, systemic and inhaled | felodipinefinasteride | nizatidinenorfloxacin |
| amoxicillin | hydrocortisone | ofloxacin |
| ampicillin, with or without sulbactam | isofluraneisoniazid | omeprazoleprednisone, prednisolone |
| atenolol | isradipine | ranitidine |
| azithromycin | influenza vaccine | rifabutin |
| caffeine, dietary ingestion | ketoconazolelomefloxacin | roxithromycinsorbitol |
| cefaclor | mebendazole | (purgative doses do not |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | medroxyprogesteronemethylprednisolone | inhibit theophylline absorption) |
| diltiazem | metronidazole | sucralfate |
| dirithromycin | metoprolol | terbutaline, systemic |
| enflurane | nadolol | terfenadine |
| famotidine | nifedipine | tetracycline |
| tocainide | ||
| *Refer to | ||
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(mg) |
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Cimetidine | 600 twice daily, 6 days |
400 single dose | 12 | 1.07 (0.77, 1.49) |
0.98 (0.81, 1.19) |
0.82 (0.69, 0.99) |
| Clarithromycin | 500 q12h, 7 days |
800 three times daily, 7 days |
10 | 1.08 (0.85, 1.38) |
1.19 (1.00, 1.42) |
1.57 (1.16, 2.12) |
| Delavirdine | 400 three times daily | 400 three times daily, 7 days |
28 | 0.64 (0.48, 0.86) |
No significant change |
2.18 (1.16, 4.12) |
| Delavirdine | 400 three times daily | 600 three times daily, 7 days |
28 | No significant change | 1.53 (1.07, 2.20) |
3.98 (2.04, 7.78) |
| Efavirenz |
600 once daily, 10 days |
1000 three times daily, 10 days |
20 | |||
| After morning dose | No significant change |
0.67 (0.61, 0.74) |
0.61 (0.49, 0.76) |
|||
| After afternoon dose | No significant change |
0.63 (0.54, 0.74) |
0.48 (0.43, 0.53) |
|||
| After evening dose | 0.71 (0.57, 0.89) |
0.54 (0.46, 0.63) |
0.43 (0.37, 0.50) |
|||
| Fluconazole |
400 once daily, 8 days |
1000 three times daily, 7 days | 11 | 0.87 (0.72, 1.05) |
0.76 (0.59, 0.98) |
0.90 (0.72, 1.12) |
| Grapefruit Juice | 8 oz. | 400 single dose | 10 | 0.65 (0.53, 0.79) |
0.73 (0.60, 0.87) |
0.90 (0.71, 1.15) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 7 days | 11 | 0.95 (0.88, 1.03) |
0.99 (0.87, 1.13) |
0.89 (0.75, 1.06) |
| Itraconazole | 200 twice daily, 7 days |
600 three times daily, 7 days |
12 | 0.78 (0.69, 0.88) |
0.99 (0.91, 1.06) |
1.49 (1.28, 1.74) |
| Ketoconazole | 400 once daily, 7 days |
600 three times daily, 7 days |
12 | 0.69 (0.61, 0.78) |
0.80 (0.74, 0.87) |
1.29 (1.11, 1.51) |
| 400 once daily, 7 days |
400 three times daily, 7 days |
12 | 0.42 (0.37, 0.47) |
0.44 (0.41, 0.48) |
0.73 (0.62, 0.85) |
|
| Methadone | 20-60 once daily in the morning, 8 days |
800 three times daily, 8 days |
10 | See text below for discussion of interaction. | ||
| Quinidine | 200 single dose | 400 single dose | 10 | 0.96 (0.79, 1.18) |
1.07 (0.89, 1.28) |
0.93 (0.73, 1.19) |
| Rifabutin | 150 once daily in the morning, 10 days |
800 three times daily, 10 days |
14 | 0.80 (0.72, 0.89) |
0.68 (0.60, 0.76) |
0.60 (0.51, 0.72) |
| Rifabutin | 300 once daily in the morning, 10 days |
800 three times daily, 10 days |
10 | 0.75 (0.61, 0.91) |
0.66 (0.56, 0.77) |
0.61 (0.50, 0.75) |
| Rifampin | 600 once daily in the morning, 8 days |
800 three times daily, 7 days |
12 | 0.13 (0.08, 0.22) |
0.08 (0.06, 0.11) |
Not Done |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 16 |
See text below for discussion of interaction. | ||
| Ritonavir | 200 twice daily, 14 days |
800 twice daily,14 days |
9, 16 |
See text below for discussion of interaction. | ||
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| St. John's wort ( standardized to 0.3 % hypericin) |
300 three times daily with meals, 14 days |
800 three times daily | 8 | Not Available | 0.46 (0.34, 0.58) |
0.19 (0.06, 0.33) |
| Stavudine (d4T) |
40 twice daily, 7 days |
800 three times daily, 7 days |
11 | 0.95 (0.80, 1.11) |
0.95 (0.80, 1.12) |
1.13 (0.83, 1.53) |
| Trimethoprim/ Sulfamethoxazole |
800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 four times daily, 7 days |
12 | 1.12 (0.87, 1.46) |
0.98 (0.81, 1.18) |
0.83 (0.72, 0.95) |
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days |
12 | 1.06 (0.91, 1.25) |
1.05 (0.86, 1.28) |
1.02 (0.77, 1.35) |
| Zidovudine/ Lamivudine (3TC) |
200/150 three times daily, 7 days | 800 three times daily, 7 days |
6, 9 |
1.05 (0.83, 1.33) |
1.04 (0.67, 1.61) |
0.98 (0.56, 1.73) |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
|
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Strong CYP34A inhibitors (e.g. itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
|
Verapamil, diltiazem |
Do not exceed 10 mg simvastatin daily |
|
Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
|
Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| HIV-1 Protease Inhibitor: atazanavir darunavir fosamprenavir |
↑ amprenavir ↑ atazanavir ↑ darunavir |
See the complete prescribing information for fosamprenavir, atazanavir, darunavir for details on co-administration with ritonavir. |
| HIV-1 Protease Inhibitor: indinavir |
↑ indinavir | Appropriate doses for this combination, with respect to efficacy and safety, have not been established. |
| HIV-1 Protease Inhibitor: saquinavir |
↑ saquinavir | See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir. Saquinavir/ritonavir in combination with rifampin is not recommended due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together. |
| HIV-1 Protease Inhibitor: tipranavir |
↑ tipranavir | See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir. |
| Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ ritonavir | Appropriate doses of this combination with respect to safety and efficacy have not been established. |
| HIV-1 CCR5 – antagonist: maraviroc | ↑ maraviroc | See the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors. |
| Integrase Inhibitor: raltegravir |
↓ raltegravir | The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration. |
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| Analgesics, Narcotic: tramadol, propoxyphene, methadone, fentanyl |
↑ analgesics ↓ methadone ↑ fentanyl |
A dose decrease may be needed for these drugs when co-administered with ritonavir. Dosage increase of methadone may be considered. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR. |
| Anesthetic: meperidine |
↓ meperidine/ ↑ normeperidine (metabolite) | Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures). |
| Antialcoholics: disulfiram/ metronidazole |
Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Antiarrhythmics: disopyramide, lidocaine, mexiletine |
↑ antiarrhythmics | For contraindicated antiarrhythmics Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available. |
| Anticancer Agents: dasatinib, nilotinib, venetoclax, vincristine, vinblastine |
↑ anticancer agents | For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. Coadministration of venetoclax and NORVIR may increase the risk of tumor lysis syndrome. Refer to the venetoclax prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
↑↓ warfarin | Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is recommended. |
| Anticoagulant: rivaroxaban |
↑ rivaroxaban | Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding. |
| Anticonvulsants: carbamazepine, clonazepam, ethosuximide |
↑ anticonvulsants | A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available. |
| Anticonvulsants: divalproex, lamotrigine, phenytoin |
↓ anticonvulsants | A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available. |
| Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g. fluoxetine, paroxetine, tricyclics: e.g. amitriptyline, nortriptyline |
↑ antidepressants | A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: desipramine |
↑ desipramine | Dosage reduction and concentration monitoring of desipramine is recommended. |
| Antidepressant: trazodone |
↑ trazodone | Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. A lower dose of trazodone should be considered. |
| Antiemetic: dronabinol |
↑ dronabinol | A dose decrease of dronabinol may be needed when co-administered with ritonavir. |
| Antifungals: ketoconazole itraconazole voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated |
| Anti-gout: colchicine |
↑ colchicine |
|
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, adjust clarithromycin dose as follows:
|
| Antimycobacterial: bedaquiline |
↑ bedaquiline | Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk. |
| Antimycobacterial: rifabutin |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary. |
| Antimycobacterial: rifampin |
↓ ritonavir | May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered. |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone dose may be needed. |
| Antiparasitic: quinine |
↑ quinine | A dose decrease of quinine may be needed when co-administered with ritonavir. |
| Antipsychotics: perphenazine, risperidone, thioridazine |
↑ antipsychotics | For contraindicated antipsychotics, A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Antipsychotics: quetiapine |
↑ quetiapine |
|
| β-Blockers: metoprolol, timolol |
↑ beta-blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Bronchodilator: theophylline |
↓ theophylline | Increased dosage of theophylline may be required; therapeutic monitoring should be considered. |
| Calcium channel blockers: diltiazem, nifedipine, verapamil |
↑ calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Digoxin | ↑ digoxin | Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels. |
| Endothelin receptor antagonists: bosentan | ↑ bosentan |
|
| Hepatitis C direct acting antiviral: simeprevir |
↑simeprevir | It is not recommended to co-administer ritonavir with simeprevir. |
| HMG-CoA Reductase Inhibitor: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
For contraindicated HMG-CoA reductase inhibitors, Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose. If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin) |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir. |
| Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone |
↑ glucocorticoids | Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use. |
| Long-acting beta-adrenoceptor agonist: salmeterol | ↑ salmeterol | Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Oral Contraceptives or Patch Contraceptives: ethinyl estradiol |
↓ ethinyl estradiol | Alternate methods of contraception should be considered. |
| PDE5 Inhibitors: avanafil sildenafil, tadalafil, vardenafil |
↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil |
For contraindicated PDE5 inhibitors, Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated The following dose adjustments are recommended for use of tadalafil (Adcirca®) with ritonavir:
Use with increased monitoring for adverse events. |
| Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem |
↑ sedative/hypnotics | A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Sedative/hypnotics: Parenteral midazolam |
↑ midazolam | For contraindicated sedative/hypnotics, Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. |
| Stimulant: methamphetamine |
↑ methamphetamine | Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir. |
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| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone. |
| DRUG | DESCRIPTION OF INTERACTION |
| Sulfonylureas | Hypoglycemia potentiated. |
| Methotrexate |
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Increased bleeding. |
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Concentration |
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| Amiodarone | 70% | NA | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring. |
| Captopril | 58% | 39% | |
| Clarithromycin | NA | 70% | |
| Dronedarone | NA | 150% | |
| Gentamicin | 129 to 212% | NA | |
| Erythromycin | 100% | NA | |
| Itraconazole | 80% | NA | |
| Lapatinib | NA | 180% | |
| Propafenone | NA | 60 to 270% | |
| Quinidine | 100% | NA | |
| Ranolazine | 50% | NA | |
| Ritonavir | NA | 86% | |
| Telaprevir | 50% | 85% | |
| Tetracycline | 100% | NA | |
| Verapamil | 50 to 75% | NA | |
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| Atorvastatin | 22% | 15% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15 to 30% or by modifying the dosing frequency and continue monitoring. |
| Carvedilol | 16% | 14% | |
| Conivaptan | 33% | 43% | |
| Diltiazem | 20% | NA | |
| Indomethacin | 40% | NA | |
| Nefazodone | 27% | 15% | |
| Nifedipine | 45% | NA | |
| Propantheline | 24% | 24% | |
| Quinine | NA | 33% | |
| Rabeprazole | 29% | 19% | |
| Saquinavir | 27% | 49% | |
| Spironolactone | 25% | NA | |
| Telmisartan | 20 to 49% | NA | |
| Ticagrelor | 31% | 28% | |
| Tolvaptan | 30% | 20 % | |
| Trimethoprim | 22 to 28% | NA | |
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| Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole | Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. | ||
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| Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine | Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 to 40 % as necessary. | ||
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| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose Recommendation |
||
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|
Coadministered Drug |
Risperidone |
AUC |
Cmax |
|
| Enzyme (CYP2D6) Inhibitors |
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| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
|
Re-evaluate dosing. |
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20 mg/day |
4 mg/day |
1.6 |
|
Do not exceed 8 mg/day |
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40 mg/day |
4 mg/day |
1.8 |
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| Enzyme (CYP3A/ PgP inducers) Inducers |
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| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
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| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
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| Other Drugs |
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine
|
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
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| Warfarin
|
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
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| Antidiabetic agents
|
Carefully monitor blood glucose (
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, alcohol. |
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The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BUPRENEX is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of BUPRENEX until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the BUPRENEX dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
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The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase |
|
|
If concomitant use is necessary, consider increasing the BUPRENEX dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider BUPRENEX dosage reduction and monitor for signs of respiratory depression. |
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Rifampin, carbamazepine, phenytoin |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
|
|
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue BUPRENEX if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome opioid toxicity (e.g., respiratory depression, coma). |
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The use of BUPRENEX is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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|
May reduce the analgesic effect of BUPRENEX and/or precipitate withdrawal symptoms. |
|
|
Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine |
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Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
|
|
Monitor patients receiving muscle relaxants and BUPRENEX for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of BUPRENEX and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
|
|
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
|
|
Monitor patients for signs of urinary retention or reduced gastric motility when BUPRENEX is used concomitantly with anticholinergic drugs. |
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Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected. |
|
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None |
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|
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects. |
|
|
Patients who are on chronic BUPRENEX treatment should have their dose monitored if NNRTIs are added to their treatment regimen. |
|
|
efavirenz, nevirapine, etravirine, delavirdine |
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|
Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly. |
|
|
Monitor patients taking BUPRENEX and atazanavir with and without ritonavir, and dose reduction of BUPRENEX may be warranted. |
|
|
atazanavir, ritonavir |
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| Clinical Impact: | Decreased exposure of omeprazole when used concomitantly with strong inducers [see |
| Intervention: | St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see |
| |
|
| Clinical Impact: | Increased exposure of omeprazole [see |
| Intervention: | Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole. |
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|---|---|---|---|---|
| diltiazem nicardipine verapamil |
fluconazole itraconazole ketoconazole voriconazole |
azithromycin clarithromycin erythromycin quinupristin/dalfopristin |
methylprednisolone | allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodone oral contraceptives |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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|
- Coumarin Derivatives - Indandione Derivatives |
|
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
|
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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|
- Interferon-α - Interleukin-2 |
|
|
- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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↑ Nevirapine |
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↑ Nevirapine |
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↑ Nevirapine |
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↓ Nelfinavir Cmin |
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Etravirine Rilpivirine |
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Methadone |
↓ Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
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Amiodarone, disopyramide, lidocaine |
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Clarithromycin |
↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
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Carbamazepine, clonazepam, ethosuximide |
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Fluconazole |
↑ Nevirapine |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
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Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
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Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
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Cyclophosphamide |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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Ergotamine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
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Cisapride |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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Fentanyl |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
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Ethinyl estradiol and Norethindrone |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine |
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40% |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40% |
| Valproate | ↑ lamotrigine |
Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Known CYP2D6 Poor Metabolizers | Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP2D6 |
Administer half of usual dose |
| Strong CYP2D6 |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
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| Clinical Impact: | • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. · Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
| Intervention: | Monitor patients with concomitant use of naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( |
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| Clinical Impact: | Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( |
| Intervention: | • Concomitant use of naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( • Naproxen sodium tablets are not substitutes for low dose aspirin for cardiovascular protection. |
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| Clinical Impact: | • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
| Intervention: | • During concomitant use of naproxen sodium and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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| Clinical Impact: | Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
| Intervention: | During concomitant use of naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( |
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| Clinical Impact: | The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin |
| Intervention: | During concomitant use of naproxen sodium and digoxin, monitor serum digoxin levels. |
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| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
| Intervention: | During concomitant use of naproxen sodium and lithium, monitor patients for signs of lithium toxicity. |
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| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
| Intervention: | During concomitant use of naproxen sodium and methotrexate, monitor patients for methotrexate toxicity. |
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| Clinical Impact: | Concomitant use of naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity. |
| Intervention: | During concomitant use of naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function. |
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| Clinical Impact: | Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( |
| Intervention: | The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. |
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| Clinical Impact: | Concomitant use of naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
| Intervention: | · During concomitant use of naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. · NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. · In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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| Clinical Impact: | Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. |
| Intervention: | Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen sodium tablets are not recommended. |
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| Clinical Impact: | Concomitant administration of cholestyramine can delay the absorption of naproxen. |
| Intervention: | Concomitant administration of cholestyramine with naproxen sodium tablet is not recommended. |
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| Clinical Impact: | Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. |
| Intervention: | Patients simultaneously receiving naproxen sodium tablets and probenecid should be observed for adjustment of dose if required. |
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| Clinical Impact: | Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. |
| Intervention: | Patients simultaneously receiving naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. |
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• Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see |
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Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see |
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• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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• During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see |
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The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see |
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The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended. |
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Concomitant use of mfenamic acid and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cm
a
x and AUC of mefenamic acid by 125% and 36%, respectively. |
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Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events. |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
|---|---|
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine
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Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (
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| Warfarin
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Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
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| Antidiabetic agents
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Carefully monitor blood glucose (
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Hepatitis C Protease inhibitor (boceprevir) |
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(e.g,. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily* |
| Grapefruit juice |
Avoid grapefruit juice |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide
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Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
|
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
|
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Drug Class | Contraindicated | Not Recommended | Use with Caution | Comments |
|---|---|---|---|---|
|
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|
|
||
| Alpha Blockers | tamsulosin | |||
| Analgesics | methadone | alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil |
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|
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|
|
||||
| Antiarrhythmics | disopyramide, dofetilide, dronedarone, quinidine |
digoxin |
|
|
| Antibacterials | telithromycin, in subjects with severe renal impairment or severe hepatic impairment | rifabutin | telithromycin |
|
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|
||||
| Anticoagulants and Antiplatelet Drugs | ticagrelor | apixaban, rivaroxaban |
coumarins, cilostazol, dabigatran |
|
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|
||||
| Anticonvulsants | carbamazepine |
|
||
| Antidiabetics | repaglinide, saxagliptin |
|||
| Antihelmintics and Antiprotozoals | praziquantel | |||
| Antimigraine Drugs | ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine) |
eletriptan |
|
|
| Antineoplastics | irinotecan | axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib, trabectedin |
bortezomib, busulphan, docetaxel, erlotinib, gefitinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids |
|
| Antipsychotics, Anxiolytics and Hypnotics | lurasidone, oral midazolam, pimozide, triazolam |
alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone |
|
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||||
| Antivirals | simeprevir | maraviroc, indinavir, ritonavir, saquinavir |
|
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| Beta Blockers | nadolol | |||
| Calcium Channel Blockers | felodipine, nisoldipine |
other dihydropyridines, verapamil |
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||||
| Cardiovascular Drugs, Miscellaneous | Ivabradine, ranolazine |
aliskiren, sildenafil, for the treatment of pulmonary hypertension |
bosentan, riociguat |
|
| Diuretics | eplerenone |
|
||
| Gastrointestinal Drugs | cisapride | aprepitant |
|
|
| Immunosuppressants | everolimus, temsirolimus |
budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus |
||
| Lipid Regulating Drugs | lovastatin, simvastatin |
atorvastatin | The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with SPORANOX® may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. | |
| Respiratory Drugs | salmeterol | |||
| Urological Drugs | fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment |
darifenacin, vardenafil |
fesoterodine. oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine |
|
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||||
| Other | colchicine, in subjects with renal or hepatic impairment | colchicine, conivaptan, tolvaptan |
cinacalcet |
|
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|
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine
|
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (
|
| Warfarin
|
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
|
| Antidiabetic agents
|
Carefully monitor blood glucose (
|
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (
|
|
|
|
|
|
|
Avoid atorvastatin
|
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily
|
| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
||
|
|
||
|
|
||
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Drug | Effect | Clinical Comment |
|---|---|---|
| ↑ Indicates increase. ↓ Indicates decrease. a Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. |
||
|
ganciclovir |
↑ didanosine concentration |
If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine- associated toxicity. |
|
methadone |
↓ didanosine concentration |
If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. |
|
nelfinavir |
No interaction 1 hour after didanosine |
Administer nelfinavir 1 hour after didanosine delayed-release capsules. |
|
tenofovir disoproxil fumarate |
↑ didanosine concentration |
A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended.a
|
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|
|
Hepatitis C protease inhibitor (boceprevir) |
|
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|
|
(mg) |
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Cimetidine | 600 twice daily, 6 days |
400 single dose | 12 | 1.07 (0.77, 1.49) |
0.98 (0.81, 1.19) |
0.82 (0.69, 0.99) |
| Clarithromycin | 500 q12h, 7 days |
800 three times daily, 7 days |
10 | 1.08 (0.85, 1.38) |
1.19 (1.00, 1.42) |
1.57 (1.16, 2.12) |
| Delavirdine | 400 three times daily | 400 three times daily, 7 days |
28 | 0.64 (0.48, 0.86) |
No significant change |
2.18 (1.16, 4.12) |
| Delavirdine | 400 three times daily | 600 three times daily, 7 days |
28 | No significant change | 1.53 (1.07, 2.20) |
3.98 (2.04, 7.78) |
| Efavirenz |
600 once daily, 10 days |
1000 three times daily, 10 days |
20 | |||
| After morning dose | No significant change |
0.67 (0.61, 0.74) |
0.61 (0.49, 0.76) |
|||
| After afternoon dose | No significant change |
0.63 (0.54, 0.74) |
0.48 (0.43, 0.53) |
|||
| After evening dose | 0.71 (0.57, 0.89) |
0.54 (0.46, 0.63) |
0.43 (0.37, 0.50) |
|||
| Fluconazole |
400 once daily, 8 days |
1000 three times daily, 7 days | 11 | 0.87 (0.72, 1.05) |
0.76 (0.59, 0.98) |
0.90 (0.72, 1.12) |
| Grapefruit Juice | 8 oz. | 400 single dose | 10 | 0.65 (0.53, 0.79) |
0.73 (0.60, 0.87) |
0.90 (0.71, 1.15) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 7 days | 11 | 0.95 (0.88, 1.03) |
0.99 (0.87, 1.13) |
0.89 (0.75, 1.06) |
| Itraconazole | 200 twice daily, 7 days |
600 three times daily, 7 days |
12 | 0.78 (0.69, 0.88) |
0.99 (0.91, 1.06) |
1.49 (1.28, 1.74) |
| Ketoconazole | 400 once daily, 7 days |
600 three times daily, 7 days |
12 | 0.69 (0.61, 0.78) |
0.80 (0.74, 0.87) |
1.29 (1.11, 1.51) |
| 400 once daily, 7 days |
400 three times daily, 7 days |
12 | 0.42 (0.37, 0.47) |
0.44 (0.41, 0.48) |
0.73 (0.62, 0.85) |
|
| Methadone | 20-60 once daily in the morning, 8 days |
800 three times daily, 8 days |
10 | See text below for discussion of interaction. | ||
| Quinidine | 200 single dose | 400 single dose | 10 | 0.96 (0.79, 1.18) |
1.07 (0.89, 1.28) |
0.93 (0.73, 1.19) |
| Rifabutin | 150 once daily in the morning, 10 days |
800 three times daily, 10 days |
14 | 0.80 (0.72, 0.89) |
0.68 (0.60, 0.76) |
0.60 (0.51, 0.72) |
| Rifabutin | 300 once daily in the morning, 10 days |
800 three times daily, 10 days |
10 | 0.75 (0.61, 0.91) |
0.66 (0.56, 0.77) |
0.61 (0.50, 0.75) |
| Rifampin | 600 once daily in the morning, 8 days |
800 three times daily, 7 days |
12 | 0.13 (0.08, 0.22) |
0.08 (0.06, 0.11) |
Not Done |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 16 |
See text below for discussion of interaction. | ||
| Ritonavir | 200 twice daily, 14 days |
800 twice daily,14 days |
9, 16 |
See text below for discussion of interaction. | ||
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| St. John's wort ( standardized to 0.3 % hypericin) |
300 three times daily with meals, 14 days |
800 three times daily | 8 | Not Available | 0.46 (0.34, 0.58) |
0.19 (0.06, 0.33) |
| Stavudine (d4T) |
40 twice daily, 7 days |
800 three times daily, 7 days |
11 | 0.95 (0.80, 1.11) |
0.95 (0.80, 1.12) |
1.13 (0.83, 1.53) |
| Trimethoprim/ Sulfamethoxazole |
800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 four times daily, 7 days |
12 | 1.12 (0.87, 1.46) |
0.98 (0.81, 1.18) |
0.83 (0.72, 0.95) |
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days |
12 | 1.06 (0.91, 1.25) |
1.05 (0.86, 1.28) |
1.02 (0.77, 1.35) |
| Zidovudine/ Lamivudine (3TC) |
200/150 three times daily, 7 days |
800 three times daily, 7 days |
6, 9 |
1.05 (0.83, 1.33) |
1.04 (0.67, 1.61) |
0.98 (0.56, 1.73) |
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
|
|
|
|
|
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
|
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aipiprazole dosage [see DOSAGE AND ADMINISTRATION ( |
|
Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
|
Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), Erythromycin | Contraindicated with lovastatin |
| Gemfibrozil, cyclosporine | Avoid with lovastatin |
| Danazol, diltiazem, dronedarone, verapamil | Do not exceed 20 mg lovastatin daily |
| Amiodarone | Do not exceed 40 mg lovastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| |
|
| |
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir), Hepatitis C Protease inhibitor (boceprevir) | Do not exceed 40 mg atorvastatin daily |
|
|
|
|
|
|
| Flouroquinolones | Take at least 2 hours before or 6 hours after Phoslyra |
| Tetracyclines | Take at least 1 hour before Phoslyra |
| Levothyroxine | Take at least 4 hours before or 4 hours after Phoslyra |
| * Refer to PRECAUTIONS, Drug Interactions for further information regarding table. | ||
| ** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. | ||
| Individual patients may experience larger changes in serum theophylline concentration than the value listed | ||
| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases theophylline clearance at allopurinol doses ≥600 mg/day. | 25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine | Similar to cimetidine |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
|
|
|
| Theophylline |
Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7) |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7) |
| Antidiabetic agents |
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7) |
| Phenytoin |
Monitor phenytoin level (7) |
| Methotrexate |
Monitor for methotrexate toxicity (7) |
| Cyclosporine |
May increase serum creatinine. Monitor serum creatinine (7) |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7) |
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Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| ↑ Indicates increase. | ||
|
|
|
|
| Drugs that may cause pancreatic toxicity | ↑risk of pancreatitis | Use only with extreme caution. |
| Neurotoxic drugs | ↑risk of neuropathy | Use with caution. |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| Lopinavir plus ritonavir | Use lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
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| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓ = Decreased (induces lamotrigine glucuronidation). | ||
| ↑ = Increased (inhibits lamotrigine glucuronidation). | ||
| ? = Conflicting data. | ||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| Concomitant Drug Class: Drug Name | Effect | Clinical Comment |
|---|---|---|
|
|
||
| Protease inhibitor: atazanavir |
↓atazanavir ↑ tenofovir |
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. |
| Protease inhibitor: fosamprenavir calcium |
↓ amprenavir | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: indinavir |
↓ indinavir | The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Protease inhibitor: lopinavir/ritonavir |
↓ lopinavir ↑ tenofovir |
Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. |
| Protease inhibitor: ritonavir |
↑ ritonavir ↑ efavirenz |
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. |
| Protease inhibitor: saquinavir |
↓ saquinavir | Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
| CCR5 co-receptor antagonist: maraviroc |
↓ maraviroc | Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA. |
| NRTI: didanosine |
↑ didanosine | Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information. |
| NNRTI: Other NNRTIs |
↑ or ↓ efavirenz and/or NNRTI | Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs. |
| Integrase strand transfer inhibitor: raltegravir |
↓ raltegravir | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
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| Protease inhibitor: boceprevir |
↓ boceprevir | Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided. |
| Protease inhibitor: simeprevir |
↓ simeprevir ↔ efavirenz |
Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir. |
| NS5A inhibitor/NS5B polymerase inhibitor : ledipasvir/sofosbuvir |
↑ tenofovir | Patients receiving ATRIPLA and HARVONI® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF. |
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| Anticoagulant: warfarin |
↑ or ↓ warfarin | Plasma concentrations and effects potentially increased or decreased by efavirenz. |
| Anticonvulsants: carbamazepine |
↓ carbamazepine ↓ efavirenz |
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. |
| phenytoin phenobarbital |
↓ anticonvulsant ↓ efavirenz |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants: bupropion |
↓ buproprion | The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| sertraline | ↓ sertraline | Increases in sertraline dose should be guided by clinical response. |
| Antifungals: itraconazole |
↓ itraconazole ↓ hydroxy-itraconazole |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| ketoconazole | ↓ ketoconazole | Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. |
| posaconazole | ↓ posaconazole | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective: clarithromycin |
↓ clarithromycin ↑ 14-OH metabolite |
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA. |
| Antimycobacterial: rifabutin |
↓ rifabutin | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| rifampin | ↓ efavirenz | If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended. |
| Antimalarials: artemether/lumefantrine |
↓ artemether ↓ dihydroartemisinin ↓ lumefantrine |
Artemether/lumefantrine should be used cautiously with ATRIPLA because decreased artemether, dihydroartemisinin (active metabolite of artemether), and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of artemether/lumefantrine. |
| Calcium channel blockers: diltiazem |
↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. |
| Others (e.g., felodipine, nicardipine, nifedipine, verapamil) |
↓ calcium channel blocker | No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin |
↓ atorvastatin ↓ pravastatin ↓ simvastatin |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: | ||
| Oral: ethinyl estradiol/norgestimate |
↓ active metabolites of norgestimate | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant: etonogestrel |
↓ etonogestrel | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immuno-suppressant | Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. |
| Narcotic analgesic: methadone |
↓ methadone | Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
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| AED Coadministered | Dose of AED (mg/day) | Oxcarbazepine Dose (mg/day) | Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) | Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine
|
400 to 2,000
|
900
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nc
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40% decrease [CI: 17% decrease, 57% decrease]
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| Phenobarbital
|
100 to 150
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600 to 1,800
|
14% increase [CI: 2% increase, 24% increase]
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25% decrease [CI: 12% decrease, 51% decrease]
|
| Phenytoin
|
250 to 500
|
600 to 1,800 >1,200 to 2,400
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nc
up to 40% increase |
30% decrease [CI: 3% decrease, 48% decrease]
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| Valproic acid
|
400 to 2,800
|
600 to 1,800
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nc
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18% decrease [CI: 13% decrease, 40% decrease]
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| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level (
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| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (
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| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (
|
| Phenytoin | Monitor phenytoin level (
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| Methotrexate | Monitor for methotrexate toxicity (
|
| Cyclosporine | May increase serum creatinine. Monitor serum creatinine (
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets (
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CYP3A4 inhibitors, e.g., ketoconazole, fluconazole |
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CYP3A4 inducers, e.g., rifampin, efavirenz |
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| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (
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Avoid atorvastatin
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| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
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Do not exceed 20 mg atorvastatin daily
|
| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Known CYP2D6 Poor Metabolizers | Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP2D6 CYP3A4 inhibitors
|
Administer half of usual dose |
| Strong CYP2D6 CYP3A4 inhibitors
|
Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
| |
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| albuterol, systemic and inhaled | hydrocortisone | ofloxacin |
| amoxicillin | isoflurane | omeprazole |
| ampicillin, with or without | isoniazid | prednisone, prednisolone |
| sulbactam | isradipine | ranitidine |
| atenolol | influenza vaccine | rifabutin |
| azithromycin | ketoconazole | roxithromycin |
| caffeine, dietary ingestion | lomefloxacin | sorbitol |
| cefaclor | mebendazole | (purgative doses do |
| co-trimoxazole (trimethoprim | medroxyprogesterone | not inhibit theophylline |
| and sulfamethoxazole) | methylprednisolone | absorption) |
| diltiazem | metronidazole | sucralfate |
| dirithromycin | metoprolol | terbutaline,systemic |
| enflurane | nadolol | terfenadine |
| famotidine | nifedipine | tetracycline |
| felodipine | nizatidine | tocainide |
| finasteride | norfloxacin | |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg. ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine ↓levonorgestrel |
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide | ↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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| Theophylline | Serious and fatal reactions. Avoid concomitant use. Monitor serum level (
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| Warfarin | Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (
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| Antidiabetic agents | Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (
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| Phenytoin | Monitor phenytoin level (
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| Methotrexate | Monitor for methotrexate toxicity (
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| Cyclosporine | May increase serum creatinine. Monitor serum creatinine (
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| Multivalent cation-containing products including antacids, metal cations, or didanosine | Decreased Ciprofloxacin absorption. Take 2 hours before or 6 hours after Ciprofloxacin (
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| 1nc denotes a mean change of less than 10% | ||||
| 2Pediatrics | ||||
| 3Mean increase in adults at high oxcarbazepine doses | ||||
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[CI: 17% decrease, 57% decrease] |
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[CI: 2% increase, 24% increase] |
[CI: 12% decrease, 51% decrease] |
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>1200 to 2400 |
up to 40% increase 3 [CI: 12% increase, 60% increase] |
[CI: 3% decrease, 48% decrease] |
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[CI: 13% decrease, 40% decrease] |
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methotrexate |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ |
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During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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· Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. · Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone |
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Concomitant use of naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Naproxen sodium is not substitutes for low dose aspirin for cardiovascular protection. |
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· NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). · In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment,co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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· During concomitant use of naproxen sodium and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. · During concomitant use of naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function · When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin |
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During concomitant use of naproxen sodium and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
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During concomitant use of naproxen sodium and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of naproxen sodium and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy |
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The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. |
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Concomitant use of naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. |
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Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen sodium is not recommended. |
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Concomitant administration of cholestyramine can delay the absorption of naproxen. |
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Concomitant administration of cholestyramine with naproxen sodium is not recommended. |
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Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. |
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Patients simultaneously receiving naproxen sodium and probenecid should be observed for adjustment of dose if required. |
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Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin |
|
|
Patients simultaneously receiving naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. |
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Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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Celecoxib has no effect on methotrexate pharmacokinetics. |
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NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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Norepinephrine Dopamine |
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| Hyperpolarization-activated cyclic nucleotide-gated channel blocker | Ivabradine | Can increase the risk of bradycardia |
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|
Concomitant use of VRAYLAR with a strong CYP3A4 inhibitor increases the exposures of cariprazine and its major active metabolite, didesmethylcariprazine (DDCAR), compared to use of VRAYLAR alone |
|
|
If VRAYLAR is used with a strong CYP3A4 inhibitor, reduce VRAYLAR dosage |
|
|
itraconazole, ketoconazole |
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|
CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine. The effect of CYP3A4 inducers on the exposure of VRAYLAR has not been evaluated, and the net effect is unclear |
|
|
Concomitant use of VRAYLAR with a CYP3A4 inducer is not recommended |
|
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rifampin, carbamazepine |
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|||
| Concentration Increase |
Increase |
|
|
| Quinidine | NA | 54-83% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. |
| Ritonavir | NA | 86% | |
| |
|||
| Amiodarone | 17% | 40% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. |
| Propafenone | 28% | 29% | |
| Quinine | NA | 34-38% | |
| Spironolactone | NA | 44% | |
| Verapamil | NA | 24% | |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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|
Inflammatory Drugs |
Agents |
|
|
| ciprofloxacin |
melphalan | amphotericin B |
azapropazon |
cimetidine |
tacrolimus |
fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate |
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3 mg twice daily |
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| Antiarrhythmics:
Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin |
Not Recommended Use With Caution |
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
|
| Oral Anticoagulants:
Warfarin |
Use With Caution |
|
|
| Antiepileptics:
Carbamazepine |
Use With Caution |
|
|
| Antifungals:
Itraconazole Fluconazole |
Use With Caution No Dose Adjustment |
|
|
| Anti-Gout Agents:
Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function) |
Contraindicated Use With Caution |
|
|
| Antipsychotics:
Pimozide Quetiapine |
Contraindicated |
|
|
| Antispasmodics:
Tolterodine (patients deficient in CYP2D6 activity) |
Use With Caution |
|
|
| Antivirals:
Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine |
Use With Caution No Dose Adjustment |
Maraviroc Zidovudine: |
|
| Calcium Channel Blockers:
Verapamil Amlodipine Diltiazem Nifedipine |
Use With Caution |
|
|
| Ergot Alkaloids:
Ergotamine Dihydroergotamine |
Contraindicated |
|
|
| Gastroprokinetic Agents:
Cisapride |
Contraindicated |
|
|
| HMG-CoA Reductase Inhibitors:
Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin |
Contraindicated Use With Caution No Dose Adjustment |
|
|
| Hypoglycemic Agents:
Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin |
Use With Caution |
|
|
| Immunosuppressants:
Cyclosporine Tacrolimus |
Use With Caution |
|
|
| Phosphodiesterase inhibitors:
Sildenafil Tadalafil Vardenafil |
Use With Caution |
|
|
| Proton Pump Inhibitors:
Omeprazole |
No Dose Adjustment |
|
|
| Xanthine Derivatives:
Theophylline |
Use With Caution |
|
|
| Triazolobenzodiazepines and Other Related Benzodiazepines:
Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam |
Use With Caution No Dose Adjustment |
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
|
| Cytochrome P450 Inducers:
Rifabutin |
Use With Caution |
|
|
| Other Drugs
Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution |
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. |
|
| Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
Hexobarbital Phenytoin Valproate |
Use With Caution |
There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. |
|
|
Drugs that Affect Clarithromycin |
|||
|
|
Recommendation |
Comments |
|
| Antifungals:
Itraconazole |
Use With Caution |
|
|
| Antivirals:
Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function) |
Use With Caution No Dose Adjustment |
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. |
|
| Proton Pump Inhibitors:
Omeprazole |
Use With Caution |
|
|
| Miscellaneous Cytochrome P450 Inducers:
Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine |
Use With Caution |
Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above). |
|
| Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements. | |
|
|
|
| Phenobarbital Rifampin |
Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine. |
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| a Should be administered at least 4 hours prior to WELCHOL | |
|
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an |
|
| c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL. | |
| Drugs with a known interaction with colesevelam | Cyclosporinec, glyburidea, levothyroxinea, and oral contraceptives containing ethinyl estradiol and norethindronea |
| Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL | phenytoina, warfarinb |
| Drugs that do not interact with colesevelam based on |
cephalexin, ciprofloxacin, digoxin, warfarinb fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil |
|
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|
|
Decreased exposure of omeprazole when used concomitantly with strong inducers |
|
|
St. John’s Wort, rifampin: Avoid concomitant use with omeprazole Ritonavir-containing products: see prescribing information for specific drugs. |
|
|
|
|
|
Increased exposure of omeprazole |
|
|
Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole. |
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|
| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
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|||||
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|||
| Antiarrhythmics:
|
|||||
| Disopyramide
Quinidine Dofetilide Amiodarone Sotalol Procainamide |
Not Recommended |
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
|||
| Digoxin | Use With Caution |
|
|||
| Oral Anticoagulants:
|
|||||
| Warfarin | Use With Caution |
|
|||
| Antiepileptics:
|
|||||
| Carbamazepine | Use With Caution |
|
|||
| Antifungals:
|
|||||
| Itraconazole | Use With Caution |
|
|||
| Fluconazole | No Dose Adjustment
|
|
|||
| Anti-Gout Agents:
|
|||||
| Colchicine (in patients with renal or hepatic impairment)
|
Contraindicated |
|
|||
| Colchicine (in patients with normal renal and hepatic function) | Use With Caution | ||||
| Antipsychotics:
|
|||||
| Pimozide | Contraindicated |
|
|||
| Quetiapine |
|
||||
| Antispasmodics:
|
|||||
| Tolterodine (patients deficient in CYP2D6 activity) | Use With Caution |
|
|||
| Antivirals:
|
|||||
| Atazanavir | Use With Caution |
|
|||
| Saquinavir (in patients with decreased renal function) |
|
||||
| Ritonavir
Etravirine |
|
||||
| Maraviroc |
|
||||
| Boceprevir (in patients with normal renal function)
Didanosine |
No Dose Adjustment |
|
|||
| Zidovudine |
The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated. |
||||
| Calcium Channel Blockers:
|
|||||
| Verapamil | Use With Caution |
|
|||
| Amlodipine
Diltiazem |
|
||||
| Nifedipine |
|
||||
| Ergot Alkaloids:
|
|||||
| Ergotamine
Dihydroergotamine |
Contraindicated |
|
|||
| Gastroprokinetic Agents:
|
|||||
| Cisapride | Contraindicated |
|
|||
| HMG-CoA Reductase Inhibitors:
|
|||||
| Lovastatin
Simvastatin |
Contraindicated |
|
|||
| Atorvastatin
Pravastatin |
Use With Caution | ||||
| Fluvastatin
|
No Dose Adjustment
|
||||
| Hypoglycemic Agents:
|
|||||
| Nateglinide
Pioglitazone Repaglinide Rosiglitazone |
Use With Caution |
|
|||
| Insulin |
|
||||
| Immunosuppressants:
|
|||||
| Cyclosporine | Use With Caution |
|
|||
| Tacrolimus |
|
||||
| Phosphodiesterase inhibitors:
|
|||||
| Sildenafil
Tadalafil Vardenafil |
Use With Caution |
|
|||
| Proton Pump Inhibitors:
|
|||||
| Omeprazole | No Dose Adjustment |
|
|||
| Xanthine Derivatives:
|
|||||
| Theophylline | Use With Caution |
|
|||
| Triazolobenzodiazepines and Other Related Benzodiazepines:
|
|||||
| Midazolam | Use With Caution |
|
|||
| Alprazolam
Triazolam |
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
||||
| Temazepam
Nitrazepam Lorazepam |
No Dose Adjustment |
|
|||
| Cytochrome P450 Inducers:
|
|||||
| Rifabutin | Use With Caution |
|
|||
| Other Drugs Metabolized by CYP3A:
|
|||||
| Alfentanil
Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution | There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. | |||
| Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
|
|||||
| Hexobarbital
Phenytoin Valproate |
Use With Caution | There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
|
|||
|
|
|||||
|
|
|
|
|||
| Antifungals:
|
|||||
| Itraconazole
|
Use With Caution |
|
|||
| Antivirals:
|
|||||
| Atazanavir | Use With Caution |
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to |
|||
| Ritonavir (in patients with decreased renal function) |
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. |
||||
| Saquinavir (in patients with decreased renal function) |
|
||||
| Etravirine |
|
||||
| Saquinavir (in patients with normal renal function) | No Dose Adjustment | ||||
| Ritonavir (in patients with normal renal function)
|
|||||
| Proton Pump Inhibitors:
|
|||||
| Omeprazole | Use With Caution |
|
|||
| Miscellaneous Cytochrome P450 Inducers:
|
|||||
| Efavirenz
Nevirapine Rifampicin Rifabutin Rifapentine |
Use With Caution | Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see
|
|||
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose (5.12, |
|
|
|
|
| CYP2C9
|
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
|
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
|
| CYP1A2
|
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
|
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
|
| CYP3A4
|
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
|
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide
|
|
|
|
| Antacids, sucralfate, multivitamins, and other products containing multivalent cations | Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin | Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Classes of Drugs | ||
| Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics† |
Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics† |
Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins† |
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|||||
| Coadministered Drug
|
Dosing Schedule
|
|
Effect on Active
Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose
Recommendation |
|
|
Coadministered Drug
|
Risperidone
|
AUC
|
C
m
a
x
|
|
| Enzyme (CYP2D6)
Inhibitors |
|
|
|
|
|
| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice
daily |
1.4
|
1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day
|
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
-
|
Re-evaluate dosing.
|
|
|
20 mg/day
|
4 mg/day
|
1.6
|
-
|
Do not exceed 8 mg/day
|
|
|
40 mg/day
|
4 mg/day
|
1.8
|
-
|
|
| Enzyme (CYP3A/
PgP inducers) |
|
|
|
|
|
| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards.
Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)
Inhibitors |
|
|
|
|
|
| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not
needed |
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not
needed |
| Erythromycin
|
500 mg four times
daily |
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not
needed |
| Other Drugs
|
|
|
|
|
|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not
needed |
|
|
|
|
|
The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity • There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole. |
|
|
Rilpivirine-containing products: Concomitant use with rabeprazole sodium delayed-release tablets are contraindicated [see CONTRAINDICATIONS ( |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see WARNINGS AND PRECAUTIONS ( |
|
|
Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. |
|
|
|
|
|
Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see WARNINGS AND PRECAUTIONS ( |
|
|
A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration. |
|
|
|
|
|
Potential for increased exposure of digoxin [see CLINICAL PHARMACOLOGY ( |
|
|
Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. |
|
|
|
|
|
Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity. |
|
|
Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. |
|
|
|
|
|
Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. |
|
|
See |
| |
|
| Alprazolam, midazolam, triazolam | HMG-CoA reductase inhibitors (lovastatin, simvastatin) |
| Cisapride | Nisoldipine |
| Dofetilide | Pimozide |
| Eplerenone | Quinidine |
| Ergot alkaloids (ergotamine, dihydroergotamine) | |
| |
|
| Alfentanil, fentanyl, sulfentanil | Indinavir, saquinavir |
| Amlodipine, felodipine, nicardipine, nifedipine | Methylprednisolone |
| Bosentan | Rifabutin |
| Buspirone | Sildenafil |
| Busulfan | Sirolimus (co-administration not recommended) |
| Carbamazepine | Tacrolimus |
| Cilostazol | Telithromycin |
| Cyclosporine | Tolterodine |
| Digoxin | Trimetrexate |
| Docetaxel, paclitaxel | Verapamil |
| Oral anti-coagulants | Vinca alkaloids (vincristine, - vinblastine, vinorelbine) |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
(mg) |
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Cimetidine | 600 twice daily, 6 days |
400 single dose | 12 | 1.07 (0.77, 1.49) |
0.98 (0.81, 1.19) |
0.82 (0.69, 0.99) |
| Clarithromycin | 500 q12h, 7 days |
800 three times daily, 7 days |
10 | 1.08 (0.85, 1.38) |
1.19 (1.00, 1.42) |
1.57 (1.16, 2.12) |
| Delavirdine | 400 three times daily | 400 three times daily, 7 days |
28 | 0.64 (0.48, 0.86) |
No significant change |
2.18 (1.16, 4.12) |
| Delavirdine | 400 three times daily | 600 three times daily, 7 days |
28 | No significant change | 1.53 (1.07, 2.20) |
3.98 (2.04, 7.78) |
| Efavirenz |
600 once daily, 10 days |
1000 three times daily, 10 days |
20 | |||
| After morning dose | No significant change |
0.67 (0.61, 0.74) |
0.61 (0.49, 0.76) |
|||
| After afternoon dose | No significant change |
0.63 (0.54, 0.74) |
0.48 (0.43, 0.53) |
|||
| After evening dose | 0.71 (0.57, 0.89) |
0.54 (0.46, 0.63) |
0.43 (0.37, 0.50) |
|||
| Fluconazole |
400 once daily, 8 days |
1000 three times daily, 7 days | 11 | 0.87 (0.72, 1.05) |
0.76 (0.59, 0.98) |
0.90 (0.72, 1.12) |
| Grapefruit Juice | 8 oz. | 400 single dose | 10 | 0.65 (0.53, 0.79) |
0.73 (0.60, 0.87) |
0.90 (0.71, 1.15) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 7 days | 11 | 0.95 (0.88, 1.03) |
0.99 (0.87, 1.13) |
0.89 (0.75, 1.06) |
| Itraconazole | 200 twice daily, 7 days |
600 three times daily, 7 days |
12 | 0.78 (0.69, 0.88) |
0.99 (0.91, 1.06) |
1.49 (1.28, 1.74) |
| Ketoconazole | 400 once daily, 7 days |
600 three times daily, 7 days |
12 | 0.69 (0.61, 0.78) |
0.80 (0.74, 0.87) |
1.29 (1.11, 1.51) |
| 400 once daily, 7 days |
400 three times daily, 7 days |
12 | 0.42 (0.37, 0.47) |
0.44 (0.41, 0.48) |
0.73 (0.62, 0.85) |
|
| Methadone | 20-60 once daily in the morning, 8 days |
800 three times daily, 8 days |
10 | See text below for discussion of interaction. | ||
| Quinidine | 200 single dose | 400 single dose | 10 | 0.96 (0.79, 1.18) |
1.07 (0.89, 1.28) |
0.93 (0.73, 1.19) |
| Rifabutin | 150 once daily in the morning, 10 days |
800 three times daily, 10 days |
14 | 0.80 (0.72, 0.89) |
0.68 (0.60, 0.76) |
0.60 (0.51, 0.72) |
| Rifabutin | 300 once daily in the morning, 10 days |
800 three times daily, 10 days |
10 | 0.75 (0.61, 0.91) |
0.66 (0.56, 0.77) |
0.61 (0.50, 0.75) |
| Rifampin | 600 once daily in the morning, 8 days |
800 three times daily, 7 days |
12 | 0.13 (0.08, 0.22) |
0.08 (0.06, 0.11) |
Not Done |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 16 |
See text below for discussion of interaction. | ||
| Ritonavir | 200 twice daily, 14 days |
800 twice daily,14 days |
9, 16 |
See text below for discussion of interaction. | ||
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| St. John's wort ( standardized to 0.3 % hypericin) |
300 three times daily with meals, 14 days |
800 three times daily | 8 | Not Available | 0.46 (0.34, 0.58) |
0.19 (0.06, 0.33) |
| Stavudine (d4T) |
40 twice daily, 7 days |
800 three times daily, 7 days |
11 | 0.95 (0.80, 1.11) |
0.95 (0.80, 1.12) |
1.13 (0.83, 1.53) |
| Trimethoprim/ Sulfamethoxazole |
800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 four times daily, 7 days |
12 | 1.12 (0.87, 1.46) |
0.98 (0.81, 1.18) |
0.83 (0.72, 0.95) |
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days |
12 | 1.06 (0.91, 1.25) |
1.05 (0.86, 1.28) |
1.02 (0.77, 1.35) |
| Zidovudine/ Lamivudine (3TC) |
200/150 three times daily, 7 days |
800 three times daily, 7 days |
6, 9 |
1.05 (0.83, 1.33) |
1.04 (0.67, 1.61) |
0.98 (0.56, 1.73) |
|
|
|
|
| * Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects ** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects *** Non-Nucleoside Reverse Transcriptase Inhibitors |
||
| Rifampin* and Rifabutin* (CYP450 Induction) |
Significantly Reduced |
|
|
(CYP450 Induction) |
|
|
|
(CYP450 Induction) |
|
|
|
(CYP450 Induction) |
|
|
| Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction) |
Reduced | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
|
|
| Long Acting Barbiturates (CYP450 Induction) |
|
|
| Phenytoin* (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. Johns Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
|
|
|
|
|
|
|
|
|
(CYP3A4 Inhibition) |
|
|
| In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) | Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
|
|
(CYP3A4 Inhibition or CYP450 Induction) |
|
|
| A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) | Careful assessment of voriconazole effectiveness | |
|
|
|
|
| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
|
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone
|
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage
|
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
|
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone
|
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage
|
| Antihypertensive Drugs
|
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
|
Monitor blood pressure and adjust dose accordingly
|
| Benzodiazepines (e.g., lorazepam)
|
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone
|
Monitor sedation and blood pressure. Adjust dose accordingly.
|
|
|
|
| Anticoagulants
|
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
|
| Antiplatelet Agents
|
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
|
| Nonsteroidal Anti-Inflammatory Agents
|
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
|
| Serotonin Reuptake Inhibitors
|
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone
|
|
|
||
|
|
|
|
| Tizanidine |
Contraindicated |
Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline |
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. |
| Drugs Known to Prolong QT Interval |
Avoid Use |
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs |
Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin |
Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine |
Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs |
Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate |
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole |
Use with caution |
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin |
| Clozapine |
Use with caution |
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs |
Use with caution |
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing. |
| Sildenafil |
Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine |
Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
|
|
||
| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Probenecid |
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
| albuterol, systemic and inhaled |
diltiazem | medroxyprogesterone | roxithromycin |
| dirithromycin | methylprednisolone | sorbitol(purgative doses | |
| amoxicillin | enflurane | metronidazole | do not
inhibit theophylline absorption) |
|
sulbactam |
famotidine | metoprolol | |
| felodipine | nadolol | ||
| finasteride | nifedipine | ||
| atenolol | hydrocortisone | nizatidine | sucralfate |
| azithromycin | isoflurane | norfloxacin | terbutaline, systemic |
| caffeine,dietary ingestion | isoniazid | ofloxacin | terfenadine |
| isradipine | omeprazole | tetracycline | |
| cefaclor | influenza vaccine | prednisone | tocainide |
| prednisolone | |||
|
sulfamethoxazole) |
ketoconazole | mebendazole | ranitidine |
| lomefloxacin | rifabutin |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| ↑ Indicates increase. ↓ Indicates decrease. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX is recommended [ b [ |
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| Interacting Agents | Prescribing Recommendations |
|---|---|
| Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with ezetimibe and simvastatin tablets |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg/10 mg ezetimibe and simvastatin tablets daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets daily |
| Lomitapide | For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets daily |
| Grapefruit juice | Avoid grapefruit juice |
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| a Should be administered at least 4 hours prior to WELCHOL | |
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b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an |
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| d Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs. | |
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| Drugs with a known interaction with colesevelam: Decrease in exposure of coadministered drug |
cyclosporinec, glimepiridea, glipizidea, glyburidea, levothyroxinea, olmesartan medoxomila, and oral contraceptives containing ethinyl estradiol and norethindronea |
| Drugs with a known interaction with colesevelam: Increase in exposure of coadministered drug |
metformin extended release (ER)d |
| Drug(s) with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL |
phenytoina, warfarinb |
| Drugs that do not interact with colesevelam based on |
aspirin, atenolol, cephalexin, ciprofloxacin, digoxin, enalapril, fenofibrate, lovastatin, metformin, metoprolol, phenytoina, pioglitazone, rosiglitazone, quinidine, repaglinide, sitagliptin, valproic acid, verapamil, warfarinb |
| Coadministered drug (Postulated effect on CYP450/UGT) | Dose schedules | Effect on asenapine pharmacokinetics | Recommendation | ||
|---|---|---|---|---|---|
| Coadministered drug | Asenapine | Cmax | AUC0–∞ | ||
| Fluvoxamine (CYP1A2 inhibitor) |
25 mg twice daily for 8 days | 5 mg Single Dose | +13% | +29% | Coadminister with caution |
| Paroxetine (CYP2D6 inhibitor) |
20 mg once daily for 9 days | 5 mg Single Dose | –13% | –9% | No SAPHRIS dose adjustment required |
| Imipramine (CYP1A2/2C19/3A4 inhibitor) | 75 mg Single Dose | 5 mg Single Dose | +17% | +10% | No SAPHRIS dose adjustment required |
| Cimetidine (CYP3A4/2D6/1A2 inhibitor) | 800 mg twice daily for 8 days | 5 mg Single Dose | –13% | +1% | No SAPHRIS dose adjustment required |
| Carbamazepine (CYP3A4 inducer) |
400 mg twice daily for 15 days | 5 mg Single Dose | –16% | –16% | No SAPHRIS dose adjustment required |
| Valproate (UGT1A4 inhibitor) |
500 mg twice daily for 9 days | 5 mg Single Dose | 2% | –1% | No SAPHRIS dose adjustment required |
| AED co-administered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazaepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400mg/day | 13% decrease |
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Glucocorticoids Octreotide |
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Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
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Iodide(including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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| Monoamine Oxidase Inhibitors (MAOIs) | The concomitant use of MAOIs and serotonergic drugs including VIIBRYD increases the risk of serotonin syndrome. | VIIBRYD is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue |
| Other Serotonergic Drugs | The concomitant use of serotonergic drugs including VIIBRYD and other serotonergic drugs increases the risk of serotonin syndrome. | Monitor patients for signs and symptoms of serotonin syndrome, particularly during VIIBRYD initiation. If serotonin syndrome occurs, consider discontinuation of VIIBRYD and/or concomitant serotonergic drugs |
| Antiplatelet Agents and Anticoagulants | Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with VIIBRYD may potentiate the risk of bleeding. | Inform patients of the increased risk of bleeding with the concomitant use of VIIBRYD and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing VIIBRYD |
| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole) | The concomitant use of VIIBRYD and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of VIIBRYD alone |
The VIIBRYD dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor |
| Strong CYP3A4 Inducers (e.g., carbamazepine, phenytoin, rifampin) |
The concomitant use of VIIBRYD and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of VIIBRYD alone |
Based on clinical response, consider increasing the dosage of VIIBRYD, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days |
| Digoxin | Digoxin is a narrow therapeutic index drug. Concomitant use of VIIBRYD increased digoxin concentrations |
Measure serum digoxin concentrations before initiating concomitant use of VIIBRYD. Continue monitoring and reduce digoxin dose as necessary. |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
| LABORATORY TESTS | EFFECT OF SALICYLATES |
| Thyroid Function | Decreased PBI; increased T3 uptake. |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). |
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. |
| Acetone, ketone bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling. |
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. |
| Vanilmandelic acid | False reduced values. |
| Uric acid | May increase or decrease depending on dose. |
| Prothrombin | Decreased levels; slightly increased prothrombin time. |
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. Do not coadminister the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
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Avoid atorvastatin |
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| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary | |
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Do not exceed 20 mg atorvastatin daily |
|
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily | |
| albuterol, systemic and inhaled | medroxyprogesterone |
| amoxicillin | methylprednisolone |
| ampicillin, with or without sulbactam | metronidazole |
| atenolol | metoprolol |
| azithromycin | nadolol |
| caffeine, dietary ingestion | nifedipine |
| cefaclor | nizatidine |
| co-trimoxazole | norfloxacin |
| (trimethoprim and sulfamethoxazole) | ofloxacin |
| diltiazem | omeprazole |
| dirithromycin | prednisone, prednisolone |
| enflurane | ranitidine |
| famotidine | rifabutin |
| felodipine | roxithromycin |
| finasteride | sorbitol |
| hydrocortisone | (purgative doses do not inhibit |
| isoflurane | theophylline absorption) |
| isoniazid | sucralfate |
| isradipine | terbutaline, systemic |
| influenza vaccine | terfenadine |
| ketoconazole | tetracycline |
| lomefloxacin | tocainide |
| mebendazole |
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(mg) |
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Cimetidine | 600 twice daily, 6 days |
400 single dose | 12 | 1.07 (0.77, 1.49) |
0.98 (0.81, 1.19) |
0.82 (0.69, 0.99) |
| Clarithromycin | 500 q12h, 7 days |
800 three times daily, 7 days |
10 | 1.08 (0.85, 1.38) |
1.19 (1.00, 1.42) |
1.57 (1.16, 2.12) |
| Delavirdine | 400 three times daily | 400 three times daily, 7 days |
28 | 0.64 (0.48, 0.86) |
No significant change |
2.18 (1.16, 4.12) |
| Delavirdine | 400 three times daily | 600 three times daily, 7 days |
28 | No significant change | 1.53 (1.07, 2.20) |
3.98 (2.04, 7.78) |
| Efavirenz |
600 once daily, 10 days |
1000 three times daily, 10 days |
20 | |||
| After morning dose | No significant change |
0.67 (0.61, 0.74) |
0.61 (0.49, 0.76) |
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| After afternoon dose | No significant change |
0.63 (0.54, 0.74) |
0.48 (0.43, 0.53) |
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| After evening dose | 0.71 (0.57, 0.89) |
0.54 (0.46, 0.63) |
0.43 (0.37, 0.50) |
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| Fluconazole |
400 once daily, 8 days |
1000 three times daily, 7 days | 11 | 0.87 (0.72, 1.05) |
0.76 (0.59, 0.98) |
0.90 (0.72, 1.12) |
| Grapefruit Juice | 8 oz. | 400 single dose | 10 | 0.65 (0.53, 0.79) |
0.73 (0.60, 0.87) |
0.90 (0.71, 1.15) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 7 days | 11 | 0.95 (0.88, 1.03) |
0.99 (0.87, 1.13) |
0.89 (0.75, 1.06) |
| Itraconazole | 200 twice daily, 7 days |
600 three times daily, 7 days |
12 | 0.78 (0.69, 0.88) |
0.99 (0.91, 1.06) |
1.49 (1.28, 1.74) |
| Ketoconazole | 400 once daily, 7 days |
600 three times daily, 7 days |
12 | 0.69 (0.61, 0.78) |
0.80 (0.74, 0.87) |
1.29 (1.11, 1.51) |
| 400 once daily, 7 days |
400 three times daily, 7 days |
12 | 0.42 (0.37, 0.47) |
0.44 (0.41, 0.48) |
0.73 (0.62, 0.85) |
|
| Methadone | 20-60 once daily in the morning, 8 days |
800 three times daily, 8 days |
10 | See text below for discussion of interaction. | ||
| Quinidine | 200 single dose | 400 single dose | 10 | 0.96 (0.79, 1.18) |
1.07 (0.89, 1.28) |
0.93 (0.73, 1.19) |
| Rifabutin | 150 once daily in the morning, 10 days |
800 three times daily, 10 days |
14 | 0.80 (0.72, 0.89) |
0.68 (0.60, 0.76) |
0.60 (0.51, 0.72) |
| Rifabutin | 300 once daily in the morning, 10 days |
800 three times daily, 10 days |
10 | 0.75 (0.61, 0.91) |
0.66 (0.56, 0.77) |
0.61 (0.50, 0.75) |
| Rifampin | 600 once daily in the morning, 8 days |
800 three times daily, 7 days |
12 | 0.13 (0.08, 0.22) |
0.08 (0.06, 0.11) |
Not Done |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 16 |
See text below for discussion of interaction. | ||
| Ritonavir | 200 twice daily, 14 days |
800 twice daily,14 days |
9, 16 |
See text below for discussion of interaction. | ||
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| St. John's wort ( standardized to 0.3 % hypericin) |
300 three times daily with meals, 14 days |
800 three times daily | 8 | Not Available | 0.46 (0.34, 0.58) |
0.19 (0.06, 0.33) |
| Stavudine (d4T) |
40 twice daily, 7 days |
800 three times daily, 7 days |
11 | 0.95 (0.80, 1.11) |
0.95 (0.80, 1.12) |
1.13 (0.83, 1.53) |
| Trimethoprim/ Sulfamethoxazole |
800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 four times daily, 7 days |
12 | 1.12 (0.87, 1.46) |
0.98 (0.81, 1.18) |
0.83 (0.72, 0.95) |
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days |
12 | 1.06 (0.91, 1.25) |
1.05 (0.86, 1.28) |
1.02 (0.77, 1.35) |
| Zidovudine/ Lamivudine (3TC) |
200/150 three times daily, 7 days | 800 three times daily, 7 days |
6, 9 |
1.05 (0.83, 1.33) |
1.04 (0.67, 1.61) |
0.98 (0.56, 1.73) |
|
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|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
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inhibitors |
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| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate |
| Drugs Known to Prolong QT Interval |
Avoid Use | Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin. |
| Cyclosporine | Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine. |
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin |
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised. |
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil | Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine | Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
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| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Probenecid | Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
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| Corticosteroids | Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism |
| Ammonium Sulfate | Increases plasma salicylate level |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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See |
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| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| AED Coadministered (daily dose) |
IR-Oxcarbazepine (daily dose) |
Influence of IR-Oxcarbazepine on AED Concentration Mean Change [90% Confidence Interval] | Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) | Recommendation |
|---|---|---|---|---|
| Carbamazepine (400 – 2000 mg) |
900 mg | nc |
40% decrease [CI: 17% decrease, 57% decrease] |
Consider initiating Oxtellar XR® at a higher dose. Monitor and titrate dose to desired clinical effect (see |
| Phenobarbital (100 – 150 mg) |
600 – 1800 mg | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
|
| Phenytoin (250 – 500 mg) |
600 – 1800 >1200-2400 |
nc up to 40% increase [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
|
| Valproic Acid (400 – 2800 mg) |
600-1800 | nc |
18% decrease [CI: 13% decrease, 40% decrease] |
Monitor. Dose adjustment of Oxtellar XR® may not be needed. |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
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| Dopamine / Dopamine Agonists Glucocorticoids Octreotide
|
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
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| Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 |
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| Amiodarone Iodide(including iodine-containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate
|
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
|
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T , and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 |
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| Carbamazepine Hydantoins Phenobarbital Rifampin
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decreases the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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Hepatitis C protease inhibitor (boceprevir) |
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Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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|
Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( |
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Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( |
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The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics. |
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During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( |
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The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology ( |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology ( |
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Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions ( |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
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| Grapefruit juice | Avoid grapefruit juice |
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| Coadministered Drug |
Dosing Schedule |
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Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
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Risperidone Dose Recommendation |
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Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
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| Enzyme (CYP2D6) Inhibitors |
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| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
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20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
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40 mg/day |
4 mg/day |
1.8 |
- |
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| Enzyme (CYP3A/ PgP inducers) |
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| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
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| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [
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| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) | Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate
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| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)
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| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated
|
Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets is co-administered with oral antidiabetic drugs [see Adverse Reactions (
|
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| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) | To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin. | ||
| Cyclosporine | Use with caution (transient elevations in serum creatinine) | Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets is co-administered with cyclosporine. | ||
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) | The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anti-coagulant (for example, warfarin). | ||
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels | Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated. | ||
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [
|
||
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised. | ||
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. | ||
| Sildenafil | Use with caution Two-fold increase in exposure | Monitor for sildenafil toxicity [see
|
||
| Duloxetine | Avoid Use
Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity | ||
| Caffeine/Xanthine Derivatives | Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life | Ciprofloxacin tablets inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. | ||
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| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin tablets should be taken at least two hours before or six hours after Multivalent cation-containing products administration
|
Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels |
||
| Probenecid
|
Use with caution (interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin tablets serum levels)
|
Potentiation of ciprofloxacin tablets toxicity may occur.
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. |
|
| Allopurinol |
|
25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. |
|
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increase theophylline clearance. | 20% increase |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20 to 40% decrease |
| Sulfinpyrazone | Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% increase |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33 to 100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
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Norepinephrine Dopamine |
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| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and
150 mcg levonorgestrel |
↓ lamotrigine
↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%.
Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide
|
↓ lamotrigine
? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir
|
↓ lamotrigine
|
Decreased lamotrigine concentration approximately 50%.
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| Atazanavir/ritonavir
|
↓ lamotrigine
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Decreased lamotrigine AUC approximately 32%.
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| Phenobarbital/primidone
|
↓ lamotrigine
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Decreased lamotrigine concentration approximately 40%.
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| Phenytoin
|
↓ lamotrigine
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Decreased lamotrigine concentration approximately 40%.
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| Rifampin
|
↓ lamotrigine
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Decreased lamotrigine AUC approximately 40%.
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| Valproate
|
↑ lamotrigine
? valproate |
Increased lamotrigine concentrations slightly more than 2-fold.
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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Diuretic-induced sodium loss may reduce lithium clearance and increase serum lithium concentrations |
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More frequent monitoring of serum electrolyte and lithium concentrations. Reduce lithium dosage based on serum lithium concentration and clinical response |
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hydrochlorothiazide, chlorothiazide, furosemide |
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NSAID decrease renal blood flow, resulting in decreased renal clearance and increased serum lithium concentrations. |
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More frequent serum lithium concentration monitoring. Reduce lithium dosage based on serum lithium concentration and clinical response |
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indomethacin, ibuprofen, naproxen |
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Concomitant use increase steady-state serum lithium concentrations. |
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More frequent monitoring of serum lithium concentration. Reduce lithium dosage based on serum lithium concentration and clinical response |
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lisinopril, enalapril, captopril, valsartan |
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Concomitant use can precipitate serotonin syndrome. |
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Monitor patients for signs and symptoms of serotonin syndrome, particularly during lithium initiation. If serotonin syndrome occurs, consider discontinuation of lithium and/or concomitant serotonergic drugs |
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selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI), monoamine oxidase inhibitors (MAOI) |
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Concomitant use may cause lithium toxicity due to reduced renal clearance. |
| |
More frequent monitoring of serum lithium concentration. Reduce lithium dosage based on serum lithium concentration and clinical response |
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metronidazole |
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Concomitant use can lower serum lithium concentrations by increasing urinary lithium excretion. |
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More frequent serum lithium concentration monitoring. Increase lithium dosage based on serum lithium concentration and clinical response |
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acetazolamide, theophylline, sodium bicarbonate |
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Concomitant use may increase risk of toxic effects of these drugs |
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Monitor patients closely for symptoms of toxicity of methyldopa, phenytoin, and carbamazepine. |
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Concomitant use may produce hypothyroidism. |
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Monitor patients for signs or symptoms of hypothyroidism |
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potassium iodide |
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Concomitant use may increase the risk of neurologic adverse reactions in the form of ataxia, tremors, nausea, vomiting, diarrhea and/or tinnitus. |
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Monitor for neurologic adverse reactions. |
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diltiazem, nifedipine, verapamil |
| |
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Reports of neurotoxic reactions in patients treated with both lithium and an antipsychotic, ranging from extrapyramidal symptoms to neuroleptic malignant syndrome, as well as reports of an encephalopathic syndrome in few patients treated with concomitant therapy |
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Monitor for neurologic adverse reactions. |
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risperidone, haloperidol, thioridazine, fluphenazine, chlorpromazine, perphenazine, clozapine |
| |
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Lithium may prolong the effects of neuromuscular blocking agents. |
| |
Monitor for prolonged paralysis or toxicity. |
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succinylcholine, pancuronium |
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
|
| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
|
Risk of Myopathy/Rhabdomyolysis ( |
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| Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol | Contraindicated with ezetimibe and simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg/10 mg ezetimibe and simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 10 mg/20 mg ezetimibe and simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin daily* |
| Grapefruit juice | Avoid grapefruit juice |
| * For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10 mg/40 mg ezetimibe and simvastatin when taking lomitapide. | |
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• Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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• In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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• During concomitant use of naproxen delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see |
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NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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| Tizanidine |
Contraindicated |
Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline |
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. |
| Drugs Known to Prolong QT Interval |
Avoid Use |
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs |
Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin |
Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine |
Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs |
Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate |
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole |
Use with caution |
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin |
| Clozapine |
Use with caution |
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs |
Use with caution |
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing. |
| Sildenafil |
Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine |
Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
|
|
||
| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Probenecid |
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
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3 mg twice daily |
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| DRUG | DESCRIPTION OF INTERACTION |
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. |
| Acidifying Agents | Increases plasma salicylate level. |
| Alkanizing Agents | Decreased plasma salicylate levels. |
| |
|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Anti-diabetic agents |
Carefully monitor blood glucose ( |
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| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [
|
||
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) | Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate
|
||
| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)
|
||
| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated
|
Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets is co-administered with oral antidiabetic drugs [see Adverse Reactions (
|
||
| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) | To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin. | ||
| Cyclosporine | Use with caution (transient elevations in serum creatinine) | Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets is co-administered with cyclosporine. | ||
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) | The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anti-coagulant (for example, warfarin). | ||
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels | Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated. | ||
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [
|
||
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised. | ||
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. | ||
| Sildenafil | Use with caution Two-fold increase in exposure | Monitor for sildenafil toxicity [see
|
||
| Duloxetine | Avoid Use
Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity | ||
| Caffeine/Xanthine Derivatives | Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life | Ciprofloxacin tablets inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. | ||
|
|
||||
| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx®
(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin tablets should be taken at least two hours before or six hours after Multivalent cation-containing products administration
|
Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels |
||
| Probenecid
|
Use with caution (interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin tablets serum levels)
|
Potentiation of ciprofloxacin tablets toxicity may occur.
|
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Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Recommendation |
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Inhibitors |
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daily |
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Do not exceed twice the patient’s usual dose |
|
Inhibitors |
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needed |
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needed |
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daily |
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needed |
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needed |
| May Require a Decrease in Dose at Cessation of Smoking | Possible Mechanism |
|---|---|
| Acetaminophen, caffeine, imipramine, oxazepam, pentazocine, propranolol, or other beta-blockers, theophylline | Deinduction of hepatic enzymes on smoking cessation. |
| Insulin | Increase of subcutaneous insulin absorption with smoking cessation. |
| Adrenergic antagonists (e.g. prazosin, labetalol) | Decrease in circulating catecholamines with smoking cessation. |
|
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| Adrenergic agonists (e.g. isoproterenol, phenylephrine) | Decrease in circulating catecholamines with smoking cessation. |
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|
| Multivalent cation-containing
products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased
when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin
|
Effect may be enhanced. Monitor
prothrombin time, INR, watch for bleeding ( |
| Antidibetic agents
|
Carefully monitor blood glucose (
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
|
Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( |
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Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
|
|
During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology ( |
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During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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|
During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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| Monoamine Oxidase Inhibitors (MAOIs) | The concomitant use of MAOIs and serotonergic drugs including VIIBRYD increases the risk of serotonin syndrome. | VIIBRYD is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue |
| Other Serotonergic Drugs | The concomitant use of serotonergic drugs including VIIBRYD and other serotonergic drugs increases the risk of serotonin syndrome. | Monitor patients for signs and symptoms of serotonin syndrome, particularly during VIIBRYD initiation. If serotonin syndrome occurs, consider discontinuation of VIIBRYD and/or concomitant serotonergic drugs |
| Antiplatelet Agents and Anticoagulants | Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with VIIBRYD may potentiate the risk of bleeding. | Inform patients of the increased risk of bleeding with the concomitant use of VIIBRYD and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing VIIBRYD |
| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole) | The concomitant use of VIIBRYD and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of VIIBRYD alone |
The VIIBRYD dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor |
| Strong CYP3A4 Inducers (e.g., carbamazepine, phenytoin, rifampin) |
The concomitant use of VIIBRYD and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of VIIBRYD alone |
Based on clinical response, consider increasing the dosage of VIIBRYD, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days |
| Digoxin | Digoxin is a narrow therapeutic index drug. Concomitant use of VIIBRYD increased digoxin concentrations |
Measure serum digoxin concentrations before initiating concomitant use of VIIBRYD. Continue monitoring and reduce digoxin dose as necessary. |
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|
| Multivalent cation-containing products including: antacids, sucralfate, multivitamins |
Decreased moxifloxacin absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3) |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3) |
| Class IA and Class III antiarrhythmics: |
Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.5) |
| Antidiabetic agents |
Carefully monitor blood glucose. (5.11, 7.3) |
| NA – Not available/reported | ||||
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Concentration Increase |
Increase |
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|
the Pharmacokinetics of Clarithromycin |
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| Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours | Simultaneous dosing of Vardenafil and Alpha-Blocker | ||||
| Alpha-Blocker | Vardenafil 10 mg Placebo-Subtracted |
Vardenafil 20 mg Placebo-Subtracted |
Vardenafil 10 mg Placebo-Subtracted |
Vardenafil 20 mg Placebo-Subtracted |
|
| Terazosin 10 mg daily |
Standing SBP | -7 (-10, -3) | -11 (-14, -7) | -23 (-31, 16) |
-14 (-33, 11) |
| Supine SBP | -5 (-8, -2) | -7 (-11, -4) | -7 (-25, 19) |
-7 (-31, 22) |
|
| Tamsulosin 0.4 mg daily |
Standing SBP | -4 (-8, -1) | -8 (-11, -4) | -8 (-14, -2) | -8 (-14, -1) |
| Supine SBP | -4 (-8, 0) | -7 (-11, -3) | -5 (-9, -2) | -3 (-7, 0) | |
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| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
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| Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
| * For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. | |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily* |
| Grapefruit juice |
Avoid grapefruit juice |
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and saquinavir/ritonavir has not been evaluated |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
|
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( |
|
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|
|
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( |
|
|
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( |
|
|
|
|
|
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
|
|
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( |
|
|
|
|
|
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology ( |
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During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
| NA = Not available/reported | |||
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Concentration Increase |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) | The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) | The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs | Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. | Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines(e.g., lorazepam) | The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ |
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During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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**No significant effect. |
||
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| AED Coadministered | AED Concentration | Felbamate Concentration |
| Phenytoin | ↑ | ↓ |
| Valproate | ↑ | ↔** |
| Carbamazepine (CBZ) *CBZ epoxide |
↓ ↑ |
↓ |
| Phenobarbital | ↑ | ↓ |
| Interacting Agents | Prescribing Recommendations |
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone |
Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil |
Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
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|---|
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a ASTAGRAF XL dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures b High dose or double strength grapefruit juice is a c Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting |
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Metoclopramide |
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• Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity • There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole. |
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mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. |
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Amoxicillin also has drug interactions. |
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| Concomitant Drug Class: Drug Name |
Effect on Concentration |
Clinical Comment |
|---|---|---|
| HIV Antiviral Agents: Reverse Transcriptase Inhibitors | ||
| Delavirdine | ↑ nelfinavir (Cmin) ↓ delavirdine |
Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established. |
| Nevirapine | ↓ nelfinavir (Cmin) | Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established. |
| Didanosine | ↔ nelfinavir | There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food). |
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| Indinavir | ↑ nelfinavir ↑ indinavir |
Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. |
| Ritonavir | ↑ nelfinavir ↔ ritonavir |
Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established. |
| Saquinavir | ↑ nelfinavir ↑ saquinavir |
Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. |
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| Warfarin | Warfarin | Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy. |
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| Carbamazepine Phenobarbital Phenytoin |
↓ nelfinavir ↓ phenytoin |
Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration. |
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| Trazodone | ↑ trazodone | Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered. |
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| Colchicine | ↑ colchicines | Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity. Treatment of gout flares – co- administration of colchicine in patients on VIRACEPT: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
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| Rifabutin | ↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID) |
It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin. |
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| Bosentan | ↑ bosentan | Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability. |
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| Atorvastatin Rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day. |
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| Cyclosporine Tacrolimus Sirolimus |
↑ immuno-suppressants ↑ nelfinavir |
Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir. |
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| Salmeterol | ↑ salmeterol | Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
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| Fluticasone | ↑ fluticasone | Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
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| Azithromycin | ↑ azithromycin | Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted. |
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| Methadone | ↓ methadone | Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT. |
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| Ethinyl estradiol Norethindrone |
↓ ethinyl estradiol ↓ norethindrone |
Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered. |
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| Sildenafil Vardenafil Tadalafil |
↑ PDE5 Inhibitors | Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. • Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) • The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events. |
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| Omeprazole | ↓ nelfinavir | Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance. |
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| Quetiapine | ↑ quetiapine |
Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
| Concomitant Drug Name or Drug Class | Clinical Rationale and Magnitude of Drug Interaction | Clinical Recommendation |
| Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure |
Consider dose reduction
|
| Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 60% decrease in exposure | Consider dose increase |
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| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
|
| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
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| Carbamazepine |
400 to 2,000 |
900 |
nc |
40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital |
100 to 150 |
600 to 1,800 |
14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin |
250 to 500 |
600 to 1,800 >1,200 to 2,400 |
nc up to 40% increase |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid |
400 to 2,800 |
600 to 1,800 |
nc |
18% decrease [CI: 13% decrease, 40% decrease] |
| Lamotrigine |
200 |
1200 |
nc |
nc |
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Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death |
|
|
Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. |
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Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted |
|
|
A temporary withdrawal of Rabeprazole Sodium Delayed-Release Tablets may be considered in some patients receiving high dose methotrexate administration. |
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Potential for increased exposure of digoxin |
|
|
Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. |
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Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity. |
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See |
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine
|
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (
|
| Warfarin
|
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
|
| Antidiabetic agents
|
Carefully monitor blood glucose (
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|
| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (> 1 quart daily) |
| |
|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidibetic agents |
Carefully monitor blood glucose ( |
|
|
Concomitant Drug |
|
| Zidovudine |
↓ Ganciclovir ↑ Zidovudine |
Zidovudine and valganciclovir tablets each have the potential to cause neutropenia and anemia |
| Probenicid |
↑ Ganciclovir |
Patients taking probenicid and valganciclovir tablets should be monitored for evidence of ganciclovir toxicity |
| Mycophenolate Mofetil (MMF) |
↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) |
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase |
| Didanosine |
↓ Ganciclovir ↑ Didanosine |
Patients should be closely monitored for didanosine toxicity |
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| AED Coadministered | Dose of AED (mg/day) |
Oxcarbazepine Dose (mg/day) |
Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) | Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc |
40% decrease [CI:17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI:12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc up to 40% increase [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc |
18% decrease [CI:13% decrease, 40% decrease] |
| Classes of Drugs | ||
| Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics† |
Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics† |
Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins† |
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| Phenytoin
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NCor25%increase
a
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48%decrease
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| Carbamazepine(CBZ)
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NC
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40%decrease
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| CBZepoxide
b
|
NC
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NE
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| Valproic acid
|
11%decrease
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14%decrease
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| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NCatTPM dosesupto400 mg/day
|
13%decrease
|
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|
| Phenytoin
|
NCor25%increase
a
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48%decrease
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| Carbamazepine(CBZ)
|
NC
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40%decrease
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| CBZepoxide
b
|
NC
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NE
|
| Valproic acid
|
11%decrease
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14%decrease
|
| Phenobarbital
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NC
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NE
|
| Primidone
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NC
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NE
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| Lamotrigine
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NCatTPM dosesupto400 mg/day
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13%decrease
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| Atazanavir/Ritonavir* | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* | ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir* | ↓ Amprenavir ↑ Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* | ↓ Indinavir | The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* | ↓ Lopinavir | Dosing in adult patients:A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* | ↓ Nelfinavir M8 Metabolite ↓ Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir | The interaction between nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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| Efavirenz* | ↓ Efavirenz | The appropriate doses of these combinations with respect to safety and efficacy have not been established. |
| Delavirdine Etravirine Rilpivirine |
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. | |
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| Boceprevir | Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine. | Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy. |
| Telaprevir | Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir. | Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events. |
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|
Methadone* |
↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
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↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Rifabutin* | ↑ Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin* | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. | Use with caution and monitor virologic response and levels of anticonvulsants. |
|
|
↑ Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Ketoconazole* | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Itraconazole | ↓ Itraconazole | Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
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|
Plasma concentrations may be increased. | Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
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Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
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Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
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Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
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Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
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↓ Ethinyl estradiol ↓ Norethindrone |
Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine extended-release |
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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See |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio
|
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| DRUG | DESCRIPTION OF INTERACTION |
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. |
| Acidifying Agents | Increases plasma salicylate level. |
| Alkanizing Agents | Decreased plasma salicylate levels. |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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and saquinavir/ritonavir has not been evaluated |
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| Alpha Blockers |
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tamsulosin |
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| Analgesics |
methadone |
|
alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil |
|
| Antiarrhythmics |
disopyramide, dofetilide, dronedarone, quinidine |
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digoxin |
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| Antibacterials |
telithromycin, in subjects with severe renal impairment or severe hepatic impairment |
rifabutin |
telithromycin |
|
| Anticoagulants and Antiplatelet Drugs |
ticagrelor |
apixaban, rivaroxaban |
coumarins, cilostazol, dabigatran |
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| Anticonvulsants |
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carbamazepine |
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| Antidiabetics |
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repaglinide, saxagliptin |
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| Antihelmintics and Antiprotozoals |
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praziquantel |
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| Antimigraine Drugs |
ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine) |
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eletriptan |
|
| Antineoplastics |
irinotecan |
axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib trabectedin |
bortezomib, busulphan, docetaxel, erlotinib, gefitinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids |
|
| Antipsychotics, Anxiolytics and Hypnotics |
lurasidone, oral midazolam, pimozide, triazolam |
|
alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone |
Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. |
| Antivirals |
|
simeprevir |
maraviroc, indinavir, ritonavir, saquinavir |
|
| Beta Blockers |
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nadolol |
|
| Calcium Channel Blockers |
felodipine, nisoldipine |
|
other dihydropyridines, verapamil |
|
| Cardiovascular Drugs, Miscellaneous |
Ivabradine ranolazine |
aliskiren, sildenafil, for the treatment of pulmonary hypertension |
bosentan, riociguat |
The potential increase in plasma concentrations of ranolazine when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation. |
| Diuretics |
eplerenone |
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| Gastrointestinal Drugs |
cisapride |
|
aprepitant |
|
| Immunosuppres sants |
|
everolimus, temsirolimus |
budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus |
|
| Lipid Regulating Drugs |
lovastatin, simvastatin |
|
atorvastatin |
The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. |
| Respiratory Drugs |
|
salmeterol |
|
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| Urological Drugs |
fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment |
darifenacin, vardenafil |
fesoterodine. oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine |
|
| Other |
colchicine, in subjects with renal or hepatic impairment |
colchicine, conivaptan, tolvaptan |
cinacalcet |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( |
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Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology ( |
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During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. |
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During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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| Estrogen-containing oral | ↓ lamotrigine | Decreased lamotrigine concentrations |
| contraceptive | approximately 50%. | |
| preparations containing | ||
| 30 mcg ethinylestradiol | ↓ levonorgestrel | Decrease in levonorgestrel |
| and 150 mcg | component by 19%. | |
| levonorgestrel | ||
| Carbamazepine | ↓ lamotrigine | Addition of carbamazepine decreases |
| and carbamazepine epoxide | lamotrigine concentration | |
| approximately 40%. | ||
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration |
| approximately 50%. | ||
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC |
| approximately 32%. | ||
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration |
| approximately 40%. | ||
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration |
| approximately 40%. | ||
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC |
| approximately 40%. | ||
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations |
| slightly more than 2-fold. | ||
| There are conflicting study results | ||
| ? valproate | regarding effect of lamotrigine on | |
| valproate concentrations: 1) a mean 25% | ||
| decrease in valproate concentrations in | ||
| healthy volunteers, 2) no change in | ||
| valproate concentrations in controlled | ||
| clinical trials in patients with epilepsy. | ||
| ↓ = Decreased (induces lamotrigine glucuronidation). | ||
| ↑ = Increased (inhibits lamotrigine glucuronidation). | ||
| ? = Conflicting data. | ||
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20 mg simvastatin daily |
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If concomitant use is necessary, consider dosage reduction of Oxycodone Hydrochloride Capsules until stable drug effects are achieved. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) |
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The concomitant use of Oxycodone Hydrochloride Capsules and CYP3A4 inducers can decrease the plasma concentration of oxycodone After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase |
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Rifampin, carbamazepine, phenytoin |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxycodone Hydrochloride Capsules if serotonin syndrome is suspected. |
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phenelzine, tranylcypromine, linezolid |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Avoid atorvastatin | |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary | |
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Do not exceed 20 mg atorvastatin daily | |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily | |
| Table 13. Established and Other Potentially Significant Drug Interactions | ||
|---|---|---|
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ Lamotrigine | Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide | ↓ Lamotrigine | Addition of carbamazepine decreases Lamotrigine concentration approximately 40% |
| ? carbamazepine epoxide | May increase CBZ epoxide levels. | |
| Lopinavir/ritonavir | ↓ Lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ Lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40% |
| Phenytoin | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40% |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate | ↑ Lamotrigine | Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
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Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| a) This table is not all inclusive. | ||
| b) In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole coadministration, although it was highly variable between patients. | ||
| c) Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers. | ||
| Calcium | Antifungal | Macrolide |
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| diltiazem | clotrimazole | clarithromycin |
| nicardipine | fluconazole | erythromycin |
| nifedipine | itraconazole | troleandomycin |
| verapamil |
voriconazole |
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| Gastrointestinal | Other | |
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| cisapride | bromocriptine | |
| metoclopramide | chloramphenicol | |
| cimetidine | ||
| cyclosporine | ||
| danazol | ||
| ethinyl estradiol | ||
| methylprednisolone | ||
| lansoprazolec | ||
| omeprazole | ||
| protease inhibitors | ||
| nefazodone | ||
| magnesium-aluminum-hydroxide | ||
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. | |
| Alcohol | A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase | |
| Allopurinol |
Decreases theophylline clearance at allopurinol doses |
25% increase | |
| Amino glutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease | |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease | |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase | |
| Ciprofloxacin | Similar to cimetidine. | 40% increase | |
| Clarithromycin | Similar to erythromycin. | 25% increase | |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. | |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase | |
| Enoxacin | Similar to cimetidine. | 300% increase | |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. | |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. | |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase | |
| Flurazepam | Similar to diazepam. | Similar to diazepam. | |
| Fluvoxamine | Similar to cimetidine | Similar to cimetidine | |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. | |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase | |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease | |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. | |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. | |
| Lorazepam | Similar to diazepam. | Similar to diazepam. | |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. | |
| Mexiletine | Similar to disulfiram. | 80% increase | |
| Midazolam | Similar to diazepam. | Similar to diazepam. | |
| Moricizine | Increases theophylline clearance. | 25% decrease | |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. | |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase | |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. | |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline and phenytoin concentrations decrease about 40%. | |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. | |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. | |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease | |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease | |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase | |
| Thiabendazole | Decreases theophylline clearance. | 190% increase | |
| Ticlopidine | Decreases theophylline clearance. | 60% increase | |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. | |
| Verapamil | Similar to disulfiram. | 20% increase | |
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| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose Recommendation |
||
| |
Coadministered Drug |
Risperidone |
AUC |
Cmax |
|
| Enzyme (CYP2D6) Inhibitors |
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| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
|
Re-evaluate dosing. |
| |
20 mg/day |
4 mg/day |
1.6 |
|
Do not exceed 8 mg/day |
| |
40 mg/day |
4 mg/day |
1.8 |
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| Enzyme (CYP3A/ PgP inducers) Inducers |
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| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
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| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
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| Other Drugs |
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
| Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours |
Simultaneous dosing of Vardenafil and Alpha-Blocker |
||||
| Alpha-Blocker | Vardenafil 10 mg Placebo-Subtracted |
Vardenafil 20 mg Placebo-Subtracted |
Vardenafil 10 mg Placebo-Subtracted |
Vardenafil 20 mg Placebo-Subtracted |
|
| Terazosin 10 mg daily |
Standing SBP | -7 (-10, -3) | -11 (-14, -7) | -23 (-31, 16) |
-14 (-33, 11) |
| Supine SBP | -5 (-8, -2) | -7 (-11, -4) | -7 (-25, 19) |
-7 (-31, 22) |
|
| Tamsulosin 0.4 mg daily |
Standing SBP | -4 (-8, -1) | -8 (-11, -4) | -8 (-14, -2) | -8 (-14, -1) |
| Supine SBP | -4 (-8, 0) | -7 (-11, -3) | -5 (-9, -2) | -3 (-7, 0) | |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine |
Decreased lamotrigine concentrations approximately 50%. |
| |
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
| Carbamazepine and epoxide |
↓ lamotrigine |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| |
? Carbamazepine epoxide |
May increase Carbamazepine epoxide levels. |
| Lopinavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine |
Increased lamotrigine concentrations slightly more than 2-fold. |
| |
? valproate |
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Etravirine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↑ = increase, ↓ = decrease, ↔ = no change | ||
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| dolutegravir |
↓ dolutegravir ↔ etravirine |
Etravirine significantly reduced plasma concentrations of dolutegravir. Using cross-study comparisons to historical pharmacokinetic data for etravirine, dolutegravir did not appear to affect the pharmacokinetics of etravirine. |
| dolutegravir/darunavir/ritonavir |
↓ dolutegravir ↔ etravirine |
The effect of etravirine on dolutegravir plasma concentrations was mitigated by co-administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Dolutegravir should only be used with INTELENCE® when co-administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. |
| dolutegravir/lopinavir/ritonavir |
↔ dolutegravir ↔ etravirine |
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| efavirenz nevirapine |
↓ etravirine | Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered. |
| delavirdine | ↑ etravirine | Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered. |
| rilpivirine | ↓ rilpivirine ↔ etravirine |
Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and rilpivirine should not be coadministered. |
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| atazanavir (without ritonavir) |
↓ atazanavir | INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir. |
| atazanavir/ritonavir |
↓ atazanavir ↔ etravirine |
Concomitant use of INTELENCE® with atazanavir/ritonavir decreased atazanavir Cmin but it is not considered clinically relevant.. The mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir in HIV-infected patients was similar to the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir can be co-administered without dose adjustments. |
| darunavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments. |
| fosamprenavir (without ritonavir) |
↑ amprenavir | Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir. |
| fosamprenavir/ritonavir |
↑ amprenavir | Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered. |
| indinavir (without ritonavir) |
↓ indinavir | Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir. |
| lopinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments. |
| nelfinavir (without ritonavir) |
↑ nelfinavir | Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir. |
| ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg twice daily should not be co-administered. |
| saquinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments. |
| tipranavir/ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered. |
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| maraviroc |
↔ etravirine ↓ maraviroc |
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE® is needed. |
| maraviroc/darunavir/ritonavir |
↔ etravirine ↑ maraviroc |
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE® is needed. |
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digoxin |
↔ etravirine ↑ digoxin |
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. |
| amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine |
↓ antiarrhythmics | Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available. |
|
warfarin |
↑ anticoagulants | Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®. |
|
carbamazepine, phenobarbital, phenytoin |
↓ etravirine | Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
|
fluconazole voriconazole |
↑ etravirine ↔ fluconazole ↑ voriconazole |
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed. |
| Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed. | ||
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itraconazole, ketoconazole, posaconazole |
↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole |
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs. |
|
clarithromycin |
↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin |
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against |
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artemether/lumefantrine |
↔ etravirine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine |
Caution is warranted when co-administering INTELENCE® and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for INTELENCE®. |
|
rifampin, rifapentine |
↓ etravirine | Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
|
rifabutin |
↓ etravirine ↓ rifabutin ↓ 25- |
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure. |
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diazepam |
↑ diazepam | Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. |
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dexamethasone (systemic) |
↓ etravirine | Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use. |
|
St. John's wort ( |
↓ etravirine | Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered. |
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boceprevir |
↓etravirine ↑ boceprevir |
The combination of INTELENCE® and boceprevir can be used without dose adjustments. However, co-administration of INTELENCE® and boceprevir is not recommended in the presence of other drugs which may further decrease etravirine exposure. This includes, but is not limited to, darunavir/ritonavir, lopinavir/ritonavir, saquinavir/ritonavir, tenofovir disoproxil fumarate, or rifabutin. |
| telaprevir |
↔ etravirine ↓ telaprevir |
There are insufficient data to make a dosing recommendation for telaprevir when used with INTELENCE®. |
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atorvastatin fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin |
↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↑ pitavastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin |
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary. |
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cyclosporine, sirolimus, tacrolimus |
↓ immunosuppressant | INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected. |
|
buprenorphine, buprenorphine/naloxone methadone |
↔ etravirine ↓ buprenorphine ↔ norbuprenorphine ↔ methadone |
INTELENCE® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
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sildenafil tadalafil, vardenafil |
↓ sildenafil ↓ N-desmethyl-sildenafil |
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect. |
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clopidogrel |
↓ clopidogrel (active) metabolite | Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered. |
| Drug | Type of Interaction | Effect† |
| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may berequired to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg ofwhiskey) decreases theophylline clearance for up to24 hours | 30% increase |
| Allopurinol | Decreases theophylline clearance at allopurinoldoses 600 mg/day | 25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction ofmicrosomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibitingcytochrome P450 1A2 | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentratrionsof adenosine, a potent CNS depressant, whiletheophylline blocks adenosine receptors. | Larger diazepam doses may be requiredto produce desired level of sedation.Discontinuation of theophylline withoutreduction of diazepam dose may resultin respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibitinghydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea,nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophyllineclearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by asimilar amount. |
| Estrogen | Estrogen containing oral contraceptives decreasetheophylline clearance in a dose-dependentfashion. The effect of progesterone on theophyllineclearance in unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium tocatecholamines, theophylline increases release ofendogenous catecholamines. | Increased risk of ventriculararrhythmias. |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increase theophylline clearance. | 20% increase |
| Ketamine | Pharmacologic | May lower theophylline seizurethreshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achievea therapeutic serum concentrationincreased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX,higher dose MTX may have a greatereffect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% increase |
| Pancuronium | Theophylline may antagonize non-depolarizingneuromuscular blocking effects;possibly due tophosphodiesterase inhibition. | Larger dose of pancuronium may berequired to achieve neuromuscularblockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks ofconcurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance byincreasing microsomal enzyme activity. | Serum theophylline and phenytoinconcentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance andpharmacologic interaction. | 40% increase. Beta-2 blocking effectmay decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologicinteraction. | 100% increase Beta-2 blocking effectmay decrease efficacy of theophylline |
| Rifampin | Increases theophylline clearance by increasingcytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increase theophylline clearance by increasingdemethylation and hydroxylation. Decreases renalclearance of theophylline. | 20% increase |
| Tacrine | Similar to cimetidine, also increases renalclearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending ontroleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
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Monitor patients with concomitant use of indomethacin extended-release capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Concomitant use of indomethacin extended-release capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ Indomethacin extended-release capsules are not a substitute for low dose aspirin for cardiovascular protection. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of indomethacin extended-release capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin extended-release capsules and triamterene should not be administered together. Both indomethacin extended-release capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin extended-release capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. |
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Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin extended-release capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [ |
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The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of indomethacin extended-release capsules and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
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During concomitant use of indomethacin extended-release capsules and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of indomethacin extended-release capsules and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of indomethacin extended-release capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of indomethacin extended-release capsules and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. |
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Concomitant use of indomethacin extended-release capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of indomethacin extended-release capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. |
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During the concomitant use of indomethacin extended-release capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| ↑ Indicates increase. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX EC is recommended [ b [ |
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| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| voriconazole | quinupristin/ | colchicine | ||
| dalfopristin | danazol | |||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
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NC or 25% increase
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48% decrease
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| Carbamazepine (CBZ)
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NC
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40% decrease
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| CBZ epoxide
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NC
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NE
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| Valproic acid
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11% decrease
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14% decrease
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| Phenobarbital
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NC
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NE
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| Primidone
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NC
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NE
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| Lamotrigine
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NC at TPM doses up to 400 mg/day
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13% decrease
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| Drug | Type of Interaction | Effect |
|---|---|---|
| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases theophylline clearance at allopurinol doses greater than or equal to 600 mg/day. | 25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects. | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20–40% decrease |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33–100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
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| Grapefruit juice | Avoid grapefruit juice |
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Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
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| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Clarithromycin | 500 twice daily, 7 days |
800 three times daily, 7 days | 12 | 1.19 (1.02, 1.39) |
1.47 (1.30, 1.65) |
1.97 (1.58, 2.46) n=11 |
| Efavirenz | 200 once daily, 14 days |
800 three times daily, 14 days | 20 | No significant change | No significant change | -- |
| Ethinyl Estradiol (ORTHO-NOVUM 1/35) |
35 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.02 (0.96, 1.09) |
1.22 (1.15, 1.30) |
1.37 (1.24, 1.51) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 8 days | 11 | 1.34 (1.12, 1.60) |
1.12 (1.03, 1.22) |
1.00 (0.92, 1.08) |
| Methadone |
20-60 once daily in the morning, 8 days |
800 three times daily, 8 days | 12 | 0.93 (0.84, 1.03) |
0.96 (0.86, 1.06) |
1.06 (0.94, 1.19) |
| Norethindrone (ORTHO-NOVUM 1/35) |
1 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.05 (0.95, 1.16) |
1.26 (1.20, 1.31) |
1.44 (1.32, 1.57) |
| Rifabutin 150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone |
150 once daily in the morning, 10 days 300 once daily in the morning, 10 days |
800 three times daily, 10 days 800 three times daily, 10 days |
14 10 |
1.29 (1.05, 1.59) 2.34 (1.64, 3.35) |
1.54 (1.33, 1.79) 2.73 (1.99, 3.77) |
1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9 |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 4 |
1.61 (1.13, 2.29) |
1.72 (1.20, 2.48) |
1.62 (0.93, 2.85) |
| 200 twice daily, 14 days |
800 twice daily, 14 days |
9, 5 |
1.19 (0.85, 1.66) |
1.96 (1.39, 2.76) |
4.71 (2.66, 8.33) n=9, 4 |
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| Saquinavir | ||||||
| Hard gel formulation | 600 single dose | 800 three times daily, 2 days | 6 | 4.7 (2.7, 8.1) |
6.0 (4.0, 9.1) |
2.9 (1.7, 4.7) |
| Soft gel formulation | 800 single dose | 800 three times daily, 2 days | 6 | 6.5 (4.7, 9.1) |
7.2 (4.3, 11.9) |
5.5 (2.2, 14.1) |
| Soft gel formulation | 1200 single dose | 800 three times daily, 2 days | 6 | 4.0 (2.7, 5.9) |
4.6 (3.2, 6.7) |
5.5 (3.7, 8.3) |
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| Stavudine |
40 twice daily, 7 days |
800 three times daily, 7 days | 13 | 0.86 (0.73, 1.03) |
1.21 (1.09, 1.33) |
Not Done |
| Theophylline | 250 single dose (on Days 1 and 7) | 800 three times daily, 6 days (Days 2 to 7) | 12, 4 |
0.88 (0.76, 1.03) |
1.14 (1.04, 1.24) |
1.13 (0.86, 1.49) n=7, 3 |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Trimethoprim | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.18 (1.05, 1.32) |
1.18 (1.05, 1.33) |
1.18 (1.00, 1.39) |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Sulfamethoxazole | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.01 (0.95, 1.08) |
1.05 (1.01, 1.09) |
1.05 (0.97, 1.14) |
| Vardenafil | 10 single dose | 800 three times daily | 18 | See text below for discussion of interaction. | ||
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days | 12 | 0.89 (0.73, 1.09) |
1.17 (1.07, 1.29) |
1.51 (0.71, 3.20) n=4 |
| Zidovudine/ Lamivudine |
||||||
| Zidovudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
1.23 (0.74, 2.03) |
1.39 (1.02, 1.89) |
1.08 (0.77, 1.50) n=5, 5 |
| Zidovudine/ Lamivudine |
||||||
| Lamivudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
0.73 (0.52, 1.02) |
0.91 (0.66, 1.26) |
0.88 (0.59, 1.33) |
|
|
|
|---|---|
| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents, presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓=Decreased (induces lamotrigine glucuronidation). ↑=Increased (inhibits lamotrigine glucuronidation). ?=Conflicting data. |
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone
Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
| Clofibrate
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV)
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4. Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4, is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral)
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
|
|---|---|---|
| ↓= Decreased (induces lamotrigine gluronidation). |
||
| ↑= Increased (inhibits lamotrigine glucuronidation). |
||
| ?= Conflicting data. |
||
|
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
approximately 50%. |
|
|
|
|
|
CBZ epoxide |
|
concentration approximately 40%. |
|
|
|
|
|
|
|
concentration approximately 40%. |
|
|
|
concentration approximately 40% |
|
|
|
approximately 40% |
|
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|
more than 2-fold. |
|
|
25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| edema hereditary coumarin resistance hyperlipemia |
hypothyroidism nephrotic syndrome |
|
|
|
| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
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|
agents |
|
|
anticholinergic agents |
|
|
tricyclic antidepressants |
|
|
opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants |
|
|
|
man who smoked marijuana; confirmed by dechallenge and rechallenge |
|
|
mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
|
|
competitive inhibition of metabolism |
|
|
marijuana; effect similar to that following smoking tobacco |
|
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|
blockade. |
|
|
marijuana |
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|---|---|
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|
|
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
|
|
|
|
Glucocorticoids Octreotide |
|
|
|
|
|
|
|
|
Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
|
|
|
|
|
Iodide (including iodine-containing Radiographic contrast agents) |
|
|
|
|
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
|
|
|
|
|
|
|
|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
|
|
|
|
|
|
|
|
Hydantoins Phenobarbital Rifampin |
|
|
|
|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
|
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
|
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
|
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
|
|
|
|
|
- Interferon-α - Interleukin-2 |
|
|
- Somatrem - Somatropin |
|
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|
|
- (e.g., Theophylline) |
|
|
|
|
|
|
|
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
|
|
|
|
|
|
Decreased exposure of omeprazole when used concomitantly with strong inducers |
|
|
|
|
|
|
|
|
Increased exposure of omeprazole |
|
|
See prescribing information for voriconazole. |
| edema hereditary coumarin resistance hyperlipemia |
hypothyroidism nephrotic syndrome |
| Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. | |
|
|
|
| Beta-adrenergic antagonists (e.g., Propranolol > 160 mg/day) |
In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state. |
| Glucocorticoids (e.g., Dexamethasone |
Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above). |
| Other drugs: Amiodarone |
Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients. |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (
|
|
|
|
|
|
|
Avoid atorvastatin
|
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily
|
| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Laboratory Tests | Effect of Salicylates |
| Thyroid Function | Decreased PBI; increased T3 uptake |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd) |
| 5 Hydroxyindole acetic acid | False negative with fluorometric test |
| Acetone, Ketone Bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling |
| 17-OH corticosteroids | False reduced values with >4.8 g qd salicylate |
| Vanilmandelic Acid | False reduced values |
| Uric Acid | May increase or decrease depending on dose |
| Prothrombin | Decreased levels; slightly increased prothrombin time |
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| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
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|
|
(e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
|||
|
|
|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
|||
| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Adenosine | Theophylline blocks | Higher doses of adenosine |
| adenosine receptors. | may be required to achieve | |
| desired effect. | ||
| Alcohol | A single large dose of alcohol | 30% increase |
| (3 ml/kg of whiskey) decreases | ||
| theophylline clearance for up | ||
| to 24 hours | ||
| Allopurinol | Decreases theophylline clearance | 25% increase at allopurinol |
| doses ≥600 mg/day. | ||
| Amino glutethimide | Increases theophylline clearance | 25% decrease |
| by induction of microsomal enzyme | ||
| activity. | ||
| Carbamazepine | Similar to aminoglutethimide | 30% decrease |
| Cimetidine | Decreases theophylline clearance | 70% increase |
| by inhibiting cytochrome P450 1A2. | ||
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS | Larger diazepam doses |
| concentrations of adenosine, a potent | may be required to | |
| CNS depressant, while theophylline | produce desired level of | |
| blocks adenosine receptors. | sedation. Discontinuation | |
| of theophylline without | ||
| reduction of diazepam | ||
| dose may result in | ||
| respiratory depression. | ||
| Disulfiram | Decreases theophylline clearance | 50% increase |
| by inhibiting hydroxylation and | ||
| demethylation. | ||
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects. | Increased frequency of |
| nausea, nervousness, | ||
| and insomnia. | ||
| Erythromycin | Erythromycin metabolite decreases | 35% increase. |
| theophylline clearance by inhibiting | Erythromycin steady-state | |
| cytochrome P450 3A3 | serum concentrations | |
| decrease by a similar amount. | ||
| Estrogen | Estrogen containing oral contraceptives decrease theophylline | 30% increase |
| clearance in a dose-dependent fashion. | ||
| The effect of progesterone on theophylline | ||
| clearance is unknown. | ||
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the | Increased risk of ventricular |
| myocardium to catecholamines, | arrhythmias | |
| theophylline increases release of | ||
| endogenous catecholamines. | ||
| Interferon, human | Decreases theophylline clearance. | 100% increase |
| recombinant alpha-A | ||
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower theophylline |
| seizure threshold. | ||
| Lithium | Theophylline increases renal | Lithium dose required to |
| lithium clearance. | achieve a therapeutic | |
| serum concentration | ||
| increased an average of | ||
| 60%. | ||
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose |
| MTX, higher dose MTX may | ||
| have a greater effect. | ||
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize | Larger dose of pancuronium may be required to |
| non-depolarizing neuromuscular | ||
| blocking effects; possibly due to | achieve neuromuscular | |
| phosphodiesterase inhibition. | blockade. | |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two |
| weeks of concurrent PB. | ||
| Phenytoin | Phenytoin increases theophylline | Serum theophylline and |
| clearance by increasing microsomal | phenytoin concentrations | |
| enzyme activity. Theophylline decreases phenytoin absorption. | decrease about 40%. | |
| Propafenone | Decreases theophylline clearance | 40% increase. Beta-2 |
| and pharmacologic interaction. | blocking effect may | |
| decrease efficacy of theophylline. | ||
| Propranolol | Similar to cimetidine and | 100% increase. Beta-2 |
| pharmacologic interaction. | blocking effect may | |
| decrease efficacy | ||
| of theophylline. | ||
| Rifampin | Increases theophylline clearance | 20-40% decrease |
| by increasing cytochrome P450 1A2 | ||
| and 3A3 activity. | ||
| Sulfinpyrazone | Increases theophylline clearance by | 20% decrease |
| increasing demethylation and hydroxyllation. | ||
| Decreases renal clearance of | ||
| theophylline. | ||
| Tacrine | Similar to cimetidine, also increases | 90% increase |
| renal clearance of theophylline. | ||
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending |
| on troleandomycin dose. | ||
| Verapamil | Similar to disulfiram. | 20% increase |
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| Theophylline |
Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents |
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin |
Monitor phenytoin level ( |
| Methotrexate |
Monitor for methotrexate toxicity ( |
| Cyclosporine |
May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( |
| AED Co-administered | AED Concentration | TOPAMAX Concentration |
| NC = Less than 10% change in plasma concentration. NE = Not Evaluated |
||
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
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| HIV-1 Protease Inhibitor: atazanavir darunavir fosamprenavir |
↑ amprenavir ↑ atazanavir ↑ darunavir |
See the complete prescribing information for fosamprenavir, atazanavir, darunavir, for details on co-administration with ritonavir. |
| HIV-1 Protease Inhibitor: indinavir |
↑ indinavir | Appropriate doses for this combination, with respect to efficacy and safety, have not been established. |
| HIV-1 Protease Inhibitor: saquinavir |
↑ saquinavir | See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir. Saquinavir/ritonavir in combination with rifampin is not recommended, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together. |
| HIV-1 Protease Inhibitor: tipranavir |
↑ tipranavir | See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir. |
| Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ ritonavir | Appropriate doses of this combination with respect to safety and efficacy have not been established. |
| HIV-1 CCR5 – antagonist: maraviroc | ↑ maraviroc | See the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors. |
| Integrase Inhibitor: raltegravir |
↓ raltegravir | The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration. |
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| Analgesics, Narcotic: tramadol, propoxyphene, methadone, fentanyl |
↑ analgesics ↓ methadone ↑ fentanyl |
A dose decrease may be needed for these drugs when co-administered with ritonavir. Dosage increase of methadone may be considered. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR. |
| Anesthetic: meperidine |
↓ meperidine/ ↑ normeperidine (metabolite) | Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures). |
| Antialcoholics: disulfiram/metronidazole |
Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Antiarrhythmics: disopyramide, lidocaine, mexiletine |
↑ antiarrhythmics | For contraindicated antiarrhythmics Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available. |
| Anticancer Agents: dasatinib, nilotinib, venetoclax, vincristine, vinblastine |
↑ anticancer agents | For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. Coadministration of venetoclax and NORVIR may increase the risk of tumor lysis syndrome. Refer to the venetoclax prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
↑↓ warfarin | Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is recommended. |
| Anticoagulant: rivaroxaban |
↑ rivaroxaban | Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding. |
| Anticonvulsants: carbamazepine, clonazepam, ethosuximide |
↑ anticonvulsants | A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available. |
| Anticonvulsants: divalproex, lamotrigine, phenytoin |
↓ anticonvulsants | A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available. |
| Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g. fluoxetine, paroxetine, tricyclics: e.g. amitriptyline, nortriptyline |
↑ antidepressants | A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: desipramine |
↑ desipramine | Dosage reduction and concentration monitoring of desipramine is recommended. |
| Antidepressant: trazodone |
↑ trazodone | Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. A lower dose of trazodone should be considered. |
| Antiemetic: dronabinol |
↑ dronabinol | A dose decrease of dronabinol may be needed when co-administered with ritonavir. |
| Antifungal: ketoconazole itraconazole voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
For contraindicated antifungals, High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended. Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated |
| Anti-gout: colchicine |
↑ colchicine |
|
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, adjust clarithromycin dose as follows:
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| Antimycobacterial: bedaquiline |
↑ bedaquiline | Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk. |
| Antimycobacterial: rifabutin |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary. |
| Antimycobacterial: rifampin |
↓ ritonavir | May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered. |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone dose may be needed. |
| Antiparasitic: quinine |
↑ quinine | A dose decrease of quinine may be needed when co-administered with ritonavir. |
| Antipsychotics: perphenazine, risperidone, thioridazine |
↑ antipsychotics | For contraindicated antipsychotics, A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Antipsychotics: quetiapine |
↑ quetiapine |
Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
| β-Blockers: metoprolol, timolol |
↑ beta-blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Bronchodilator: theophylline |
↓ theophylline | Increased dosage of theophylline may be required; therapeutic monitoring should be considered. |
| Calcium channel blockers: diltiazem, nifedipine, verapamil |
↑ calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Digoxin | ↑ digoxin | Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels. |
| Endothelin receptor antagonists: bosentan | ↑ bosentan |
In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| Hepatitis C direct acting antiviral: simeprevir |
↑simeprevir | It is not recommended to co-administer ritonavir with simeprevir. |
| HMG-CoA Reductase Inhibitor: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
For contraindicated HMG-CoA Reductase inhibitors, Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose. If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin) |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir. |
| Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone |
↑ glucocorticoids |
Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use. |
| Long-acting beta-adrenoceptor agonist: salmeterol | ↑ salmeterol | Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Oral Contraceptives or Patch Contraceptives: ethinyl estradiol |
↓ ethinyl estradiol | Alternate methods of contraception should be considered. |
| PDE5 Inhibitors: avanafil sildenafil, tadalafil, vardenafil |
↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil |
For contraindicated PDE5 inhibitors, Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated The following dose adjustments are recommended for use of tadalafil (Adcirca®) with ritonavir: In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for the treatment of erectile dysfunction: It is recommended not to exceed the following doses:
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| Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem |
↑ sedative/hypnotics | A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Sedative/hypnotics: Parenteral midazolam |
↑ midazolam | For contraindicated sedative/hypnotics, Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. |
| Stimulant: methamphetamine |
↑ methamphetamine | Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir. |
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| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem |
Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
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NC or 25% increase
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48% decrease
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| Carbamazepine (CBZ)
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NC
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40% decrease
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| CBZ epoxide
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NC
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NE
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| Valproic acid
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11% decrease
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14% decrease
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| Phenobarbital
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NC
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NE
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| Primidone
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NC
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NE
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| Lamotrigine
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NC at TPM doses up to 400 mg/day
|
13% decrease
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|---|---|---|
| ↓ = Decreased (induces lamotrigine glucuronidation) ↑ = Increased (inhibits lamotrigine glucuronidation) ? = Conflicting data |
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epoxide |
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epoxide |
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| AED Co-administered | AED Concentration | Topiramate Concentration |
|---|---|---|
| NC = Less than 10% change in plasma concentration. | ||
| NE = Not Evaluated | ||
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12h and efavirenz should be decreased to 300 mg every 24h |
|
(400 mg every 12h)** (CYP3A4 Inhibition) Low-dose Ritonavir (100 mg every 12h)** |
Ritonavir Cmax or AUCτ Slight Decrease in Ritonavir Cmax and AUCτ |
Coadministration of voriconazole and low-dose ritonavir (100 mg every 12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
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(CYP3A4 Inhibition) |
Plasma Exposure Likely to be Increased |
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(CYP450 Inhibition) |
Plasma Exposure Likely to be Increased |
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(CYP3A4 Inhibition) |
No Significant Effect on Cmax |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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ibuprofen and diclofenac (CYP2C9 Inhibition) |
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(CYP3A4 Inhibition) |
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(CYP2C9 Inhibition) |
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ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** |
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(CYP2C9 Inhibition) |
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(CYP2C19/3A4 Inhibition) |
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(CYP3A4 Inhibition) |
In Vitro |
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors |
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(CYP3A4 Inhibition) |
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(CYP3A4 Inhibition) |
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(Statins) (CYP3A4 Inhibition) |
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Blockers (CYP3A4 Inhibition) |
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(CYP2C9 Inhibition) |
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(CYP3A4 Inhibition) |
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Norepinephrine Dopamine |
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| Concomitant Drug Class or Food | Noted or anticipated Outcome | Clinical Comment |
|---|---|---|
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atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) | Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy. |
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fibrates, gemfibrozil |
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digoxin |
P-gp substrate; rhabdomyolysis has been reported |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents,presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
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| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| Lopinavir plus ritonavir | Use lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
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| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
| NA = Not available/reported | |||
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| Clinical Impact: | Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. | |
| Intervention: |
Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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| Clinical Impact: |
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
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| Intervention: |
Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
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| Clinical Impact: | NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. | |
| Intervention: |
During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [
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| Clinical Impact: |
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [
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| Intervention: |
Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [
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| Clinical Impact: | The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. | |
| Intervention: | During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. | |
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| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. | |
| Intervention: | During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. | |
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| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). | |
| Intervention: | During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity. | |
| Intervention: | During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. | |
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| Clinical Impact: |
Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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| Intervention: | The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. | |
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| Clinical Impact: | Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). | |
| Intervention: | During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. | |
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| Clinical Impact: | When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. | |
| Intervention: | During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. | |
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Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin |
Not Recommended Use With Caution |
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
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Warfarin |
Use With Caution |
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Carbamazepine |
Use With Caution |
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Itraconazole Fluconazole |
Use With Caution No Dose Adjustment |
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Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function) |
Contraindicated Use With Caution |
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Pimozide Quetiapine |
Contraindicated |
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Tolterodine (patients deficient in CYP2D6 activity) |
Use With Caution |
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Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine |
Use With Caution No Dose Adjustment |
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Verapamil Amlodipine Diltiazem Nifedipine |
Use With Caution |
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Ergotamine Dihydroergotamine |
Contraindicated |
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Cisapride |
Contraindicated |
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Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin |
Contraindicated Use With Caution No Dose Adjustment |
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Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin |
Use With Caution |
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Cyclosporine Tacrolimus |
Use With Caution |
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Sildenafil Tadalafil Vardenafil |
Use With Caution |
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Omeprazole |
No Dose Adjustment |
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Theophylline |
Use With Caution |
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Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam |
Use With Caution No Dose Adjustment |
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
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Rifabutin |
Use With Caution |
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Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution |
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. |
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Hexobarbital Phenytoin Valproate |
Use With Caution |
There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. |
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Itraconazole |
Use With Caution |
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Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function) |
Use With Caution No Dose Adjustment |
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. |
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Omeprazole |
Use With Caution |
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Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine |
Use With Caution |
Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above). |
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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| Anticoagulants
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argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
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| Antiplatelet Agents
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aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
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| Nonsteroidal Anti-Inflammatory Agents
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celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
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| Serotonin Reuptake Inhibitors
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citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone
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The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome. |
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Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue |
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selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
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Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias. |
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Concomitant use of pimozide and sertraline hydrochloride is contraindicated |
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The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome. |
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Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs |
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other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort |
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The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding. |
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Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio |
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aspirin, clopidogrel, heparin, warfarin |
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Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma |
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Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted. |
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warfarin |
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Sertraline hydrochloride is a CYP2D6 inhibitor |
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Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued. |
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propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine |
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Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations. |
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Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed. |
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phenytoin, fosphenytoin |
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Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
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- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
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- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
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- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
|
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|
| Phenytoin
|
NCor25%increase
a
|
48%decrease
|
| Carbamazepine(CBZ)
|
NC
|
40%decrease
|
| CBZepoxide
b
|
NC
|
NE
|
| Valproic acid
|
11%decrease
|
14%decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NCatTPM dosesupto400 mg/day
|
13%decrease
|
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|
|---|---|
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| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
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Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. |
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Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen is not recommended. |
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Concomitant administration of cholestyramine can delay the absorption of naproxen. |
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Concomitant administration of cholestyramine with naproxenis not recommended. |
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Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. |
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Patients simultaneously receiving naproxen and probenecid should be observed for adjustment of dose if required. |
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Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin |
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Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. | |
| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
|
NC or 25% increase
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
|
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| Drug | Type of Interaction | Effect† |
|---|---|---|
| * † interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed. |
||
| Adenosine | Theophylline blocks adenosine
receptors. |
Higher doses of adenosine may be required to achieve
desired effect. |
| Alcohol | A single large dose of alcohol (3
mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. |
30% increase |
| Allopurinol | Decreases theophylline clearance
at allopurinol doses ≥600 mg/day. |
25% increase |
| Aminoglutethimide | Increases theophylline clearance
by induction of microsomal enzyme activity. |
25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance
by inhibiting cytochrome P450 1A2. |
70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS
concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. |
Larger diazepam doses may be required to produce
desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance
by inhibiting hydroxylation and demethylation. |
50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects. | Increased frequency of nausea, nervousness, and
insomnia. |
| Erythromycin | Erythromycin metabolite
decreases theophylline clearance by inhibiting cytochrome P450 3A3. |
35% increase. Erythromycin steady-state serum
concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral
contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown. |
30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine |
| Halothane | Halothane sensitizes the
myocardium to catecholamines, theophylline increases release of endogenous catecholamines. |
Increased risk of ventricular arrhythmias. |
| Interferon, human
recombinant alpha-A |
Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic. | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal
lithium clearance. |
Lithium dose required to achieve a therapeutic serum
concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX
may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize
non-depolarizing neuromuscular blocking effects, possibly due to phosphodiesterase inhibition. |
Larger dose of pancuronium may be required to
achieve neuromuscular blockade |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline
clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. |
Serum theophylline decrease about 40%. |
| Propafenone | Decreases theophylline clearance
and pharmacologic interaction. |
40% increase. Beta2 blocking effect may decrease
efficacy of theophylline |
| Propranolol | Similar to cimetidine and
pharmacologic interaction. |
100% increase. Beta2 blocking effect may decrease
efficacy of theophylline |
| Rifampin | Increases theophylline clearance
by increasing cytochrome P450 1A2 and 3A3 activity. |
20-40% decrease |
| St. John's Wort
(Hypericum Perforatum) |
Decrease in theophylline plasma
concentrations. |
Higher doses of theophylline may be required to
achieve desired effect. Stopping St. John's Wort may result in theophylline toxicity. |
| Sulfinpyrazone | Increases theophylline clearance
by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. |
20% decrease |
| Tacrine | Similar to cimetidine, also
increases renal clearance of theophylline. |
90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
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| Amprenavir |
1200 mg BID x 10 days |
300 mg QD x 10 days |
Healthy male subjects (6) |
↑ AUC by 193%, ↑ Cm
a
x by 119% |
↔ |
Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions. |
| Delavirdine |
400 mg TID |
300 mg QD |
HIV-infected patients (7) |
↑ AUC by 230%, ↑ Cm
a
x by 128% |
↓ AUC by 80%, ↓ Cmax by 75%, ↓ Cm i n by 17% |
|
| Didanosine |
167 or 250 mg BID x 12 days |
300 or 600 mg QD x 1 |
HIV-infected patients (11) |
↔ |
↔ |
|
| Fosamprenavir/ ritonavir |
700 mg BID plus ritonavir 100 mg BID x 2 weeks |
150 mg every other day x 2 weeks |
Healthy subjects (15) |
↔ AUCa
↓ Cm
a
x by 15% |
↑ AUC by 35%b, ↑ Cm a x by 36%, ↑ Cm i n by 36% |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination. |
| Indinavir |
800 mg TID x 10 days |
300 mg QD x 10 days |
Healthy subjects (10) |
↑ AUC by 173%, ↑ Cmax by 134% |
↓ AUC by 34%, ↓ Cm
a
x by 25%, ↓ Cm
i
n by 39% |
Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID. |
| Lopinavir/ ritonavir |
400/100 mg BID x 20 days |
150 mg QD x 10 days |
Healthy subjects (14) |
↑ AUC by 203%c
↓ Cm a x by 112% |
↔ |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Saquinavir/ ritonavir |
1000/100 mg BID x 14 or 22 days |
150 mg every 3 days X 21 to 22 days |
Healthy subjects |
↑ AUC by 53% d ↑ Cm
a
x by 88% (n=11) |
↓ AUC by 13%, ↓ Cm
a
x by 15%, (n=19) |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions. |
| Ritonavir |
500 mg BID x 10 days |
150 mg QD x 16 days |
Healthy subjects (5) |
↑ AUC by 300%, ↑ Cm
a
x by 150% |
ND |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Tipranavir/ ritonavir |
500/200 BID X 15 doses |
150 mg single dose |
Healthy subjects (20) |
↑ AUC by 190%, ↑ Cm
a
x by 70% |
↔ |
Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed. |
| Nelfinavir |
1250 mg BID x 7 to 8 days |
150 mg QD x 8 days |
HIV-infected patients (11) |
↑ AUC by 83%,e ↑ Cm
a
x by 19% |
↔ |
Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID |
| Zidovudine |
100 or 200 mg q4h |
300 or 450 mg QD |
HIV-infected patients (16) |
↔ |
↓ AUC by 32%, ↓ Cm
a
x by 48% |
Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary. |
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| Fluconazole |
200 mg QD x 2 weeks |
300 mg QD x 2 weeks |
HIV-infected patients (12) |
↑ AUC by 82%, ↑ Cm
a
x by 88% |
↔ |
Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected. |
| Posaconazole |
200 mg QD x 10 days |
300 mg QD x 17 days |
Healthy subjects (8) |
↑ AUC by 72%, ↑ Cm
a
x by 31% |
↓ AUC by 49%, ↓ Cm
a
x by 43% |
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy. |
| Itraconazole |
200 mg QD |
300 mg QD |
HIV-Infected patients (6) |
↑f
|
↓ AUC by 70%, ↓ Cm
a
x by 75% |
If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following coadministration of rifabutin (300 mg QD) with itraconazole (600 to 900 mg QD). |
| Voriconazole |
400 mg BID x 7 days (maintenance dose) |
300 mg QD x 7 days |
Healthy male subjects (12) |
↑ AUC by 331%, ↑ Cm
a
x by 195% |
↑ AUC by ~100%, ↑ Cm a x by ~100%g |
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| Dapsone |
50 mg QD |
300 mg QD |
HIV-infected patients (16) |
ND |
↓ AUC by 27 to 40% |
|
| Sulfamethoxazole-Trimethoprim |
800/160 mg |
300 mg QD |
HIV-infected patients (12) |
↔ |
↓ AUC by 15 to 20% |
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| Azithromycin |
500 mg QD x 1 day, then 250 mg QD x 9 days |
300 mg QD |
Healthy subjects (6) |
↔ |
↔ |
|
| Clarithromycin |
500 mg BID |
300 mg QD |
HIV-infected patients (12) |
↑ AUC by 75% |
↓ AUC by 50% |
Monitor for rifabutin associated adverse events. Reduce dose or suspend use of rifabutin if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin |
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| Ethambutol |
1200 mg |
300 mg QD X 7 days |
Healthy subjects (10) |
ND |
↔ |
|
| Isoniazid |
300 mg |
300 mg QD X 7 days |
Healthy subjects (6) |
ND |
↔ |
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| Methadone |
20 to 100 mg QD |
300 mg QD X 13 days |
HIV-infected patients (24) |
ND |
↔ |
|
| Ethinylestradiol (EE)/ Norethindrone (NE) |
35 mg EE / 1 mg NE X 21 days |
300 mg QD X 10 days |
Healthy female subjects (22) |
ND |
EE: ↓ AUC by 35%, ↓ Cmax by 20% NE: ↓ AUC by 46% |
Patients should be advised to use additional or alternative methods of contraception. |
| Theophylline |
5 mg/kg |
300 mg X 14 days |
Healthy subjects (11) |
ND |
↔ |
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| Drug/Drug Class (Mechanism of Interaction by the Drug) |
Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg q12h) |
Recommendations for Voriconazole Dosage Adjustment/Comments |
|---|---|---|
| Rifampin (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (400 mg q24h) (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (300 mg q24h) (CYP450 Induction) |
Slight Decrease in AUC |
When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) Low-dose Ritonavir (100 mg q12h) |
Significantly Reduced Reduced |
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John's Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole |
Significantly Increased | Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
| Other NNRTIs (CYP3A4 Inhibition or CYP450 Induction) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness |
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| Tizanidine |
Contraindicated |
Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline |
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate |
| Drugs Known to Prolong QT Interval |
Avoid Use |
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs |
Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin |
Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine |
Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs |
Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate |
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole |
Use with caution |
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin |
| Clozapine |
Use with caution |
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs |
Use with caution |
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil |
Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine |
Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
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| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Probenecid |
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
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| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| AED co-administered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazaepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400mg/day | 13% decrease |
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See prescribing information for voriconazole. |
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3 mg twice daily |
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Norepinephrine Dopamine |
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| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
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Dofetilide | Concomitant administration with digoxin was associated with a higher rate of torsades de pointes. |
| Moricizine | Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction. | |
| Sotalol | Proarrhythmic events even more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving dioxin. | |
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Teriparatide | Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. |
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Thyroid | Treatment of hyperthyroidism in patients taking digoxin may increase the dose requirements of digoxin. |
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Epinepherine | Can increase the risk of cardiac arrhythmias. |
| Norepinephrine | ||
| Dopamine | ||
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Succinylcholine | May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin. |
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Calcium | If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. |
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Additive effects on AV node conduction can result in complete heart block. | |
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(Cmax and AUCτ) |
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| (CYP3A4 Inhibition) |
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| (CYP3A4 Inhibition) |
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| (CYP3A4 Inhibition) |
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| (CYP450 Inhibition) |
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| (CYP3A4 Inhibition) |
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| (CYP3A4 Inhibition) |
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| (CYP3A4 Inhibition) |
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| (CYP3A4 Inhibition) |
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| (CYP3A4 Inhibition) |
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Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Known CYP2D6 Poor Metabolizers
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Administer half of usual dose
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| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
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Administer a quarter of usual dose
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| Strong CYP2D6 or CYP3A4 inhibitors
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Administer half of usual dose
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| Strong CYP2D6 and CYP3A4
inhibitors |
Administer a quarter of usual dose
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| Strong CYP3A4 inducers
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Double usual dose over 1 to 2 weeks
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| NA = Not available/reported | |||
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Concentration Increase |
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(Plasma Exposure Likely to be Increased and Prolonged) |
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Five-fold increase in duloxetine exposure |
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(didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
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| 5-lipoxygenase Inhibitor | Antiplatelet Drugs/Effects | Leukotriene Receptor Antagonist |
| Adrenergic Stimulants, Central | Antithyroid Drugs† | Monoamine Oxidase Inhibitors |
| Alcohol Abuse Reduction | Beta-Adrenergic Blockers | Narcotics, prolonged |
| Preparations | Cholelitholytic Agents | Nonsteroidal Anti- |
| Analgesics | Diabetes Agents, Oral | Inflammatory Agents |
| Anesthetics, Inhalation | Diuretics† | Proton Pump Inhibitors |
| Antiandrogen | Fungal Medications, | Psychostimulants |
| Antiarrhythmics† | Intravaginal, Systemic† | Pyrazolones |
| Antibiotics† | Gastric Acidity and Peptic | Salicylates |
| Aminoglycosides (oral) | Ulcer Agents† | Selective Serotonin |
| Cephalosporins, parenteral | Gastrointestinal | Reuptake Inhibitors |
| Macrolides | Prokinetic Agents | Steroids, Adrenocortical† |
| Miscellaneous | Ulcerative Colitis Agents | Steroids, Anabolic (17-Alkyl |
| Penicillins, intravenous, | Gout Treatment Agents | Testosterone Derivatives) |
| high dose | Hemorrheologic Agents | Thrombolytics |
| Quinolones (fluoroquinolones) | Hepatotoxic Drugs | Thyroid Drugs |
| Sulfonamides, long acting | Hyperglycemic Agents | Tuberculosis Agents† |
| Tetracyclines | Hypertensive Emergency Agents | Uricosuric Agents |
| Anticoagulants | Hypnotics† | Vaccines |
| Anticonvulsants† | Hypolipidemics† | Vitamins† |
| Antidepressants† | Bile Acid-Binding Resins† | |
| Antimalarial Agents | Fibric Acid Derivatives | |
| Antineoplastics† | HMG-CoA Reductase Inhibitors† | |
| Antiparasitic/Antimicrobials | ||
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| acetaminophen | fenoprofen | paroxetine |
| alcohol |
fluconazole | penicillin G, intravenous |
| allopurinol | fluorouracil | pentoxifylline |
| aminosalicylic acid | fluoxetine | phenylbutazone |
| amiodarone HCl | flutamide | phenytoin |
| argatroban | fluvastatin | piperacillin |
| aspirin | fluvoxamine | piroxicam |
| atenolol | gefitinib | pravastatin |
| atorvastatin |
gemfibrozil | prednisone |
| azithromycin | glucagon | propafenone |
| bivalirudin | halothane | propoxyphene |
| capecitabine | heparin | propranolol |
| cefamandole | ibuprofen | propylthiouracil |
| cefazolin | ifosfamide | quinidine |
| cefoperazone | indomethacin | quinine |
| cefotetan | influenza virus vaccine | rabeprazole |
| cefoxitin | itraconazole | ranitidine |
| ceftriaxone | ketoprofen | rofecoxib |
| celecoxib | ketorolac | sertraline |
| cerivastatin | lansoprazole | simvastatin |
| chenodiol | lepirudin | stanozolol |
| chloramphenicol | levamisole | streptokinase |
| chloral hydrate |
levofloxacin | sulfamethizole |
| chlorpropamide | levothyroxine | sulfamethoxazole |
| cholestyramine |
liothyronine | sulfinpyrazone |
| cimetidine | lovastatin | sulfisoxazole |
| ciprofloxacin | mefenamic acid | sulindac |
| cisapride | methimazole |
tamoxifen |
| clarithromycin | methyldopa | tetracycline |
| clofibrate | methylphenidate | thyroid |
| warfarin sodium overdose | methylsalicylate ointment (topical) | ticarcillin |
| cyclophosphamide |
metronidazole | ticlopidine |
| danazol | miconazole | tissue plasminogen |
| dextran | (intravaginal, oral, systemic) | activator (t-PA) |
| dextrothyroxine | moricizine hydrochloride |
tolbutamide |
| diazoxide | nalidixic acid | tramadol |
| diclofenac | naproxen | trimethoprim/sulfamethoxazole |
| dicumarol | neomycin | urokinase |
| diflunisal | norfloxacin | valdecoxib |
| disulfiram | ofloxacin | valproate |
| doxycycline | olsalazine | vitamin E |
| erythromycin | omeprazole | zafirlukast |
| esomeprazole | oxandrolone | zileuton |
| ethacrynic acid | oxaprozin | |
| ezetimibe | oxymetholone | |
| fenofibrate | pantoprazole | |
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Naproxen may decrease platelet aggregation and prolong bleeding time. |
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This effect should be kept in mind when bleeding times are determined. |
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The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. |
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Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with NAPRELAN be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. |
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Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). |
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This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid are determined. |
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| Digoxin Enalapril Iron Metoprolol Warfarin |
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Ciprofloxacin Mycophenolate mofetil |
Take at least 2 hours before or 6 hours after sevelamer Take at least 2 hours before sevelamer |
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| Clinical Impact | Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. |
| Intervention | Do not administer MAS-ER Capsules concomitantly or within 14 days after discontinuing MAOI |
| Examples | selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
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| Clinical Impact | The concomitant use of MAS-ER Capsules and serotonergic drugs increases the risk of serotonin syndrome. |
| Intervention | Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during MAS-ER Capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the concomitant serotonergic drug(s) |
| Examples | selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort |
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| Clinical Impact | The concomitant use of MAS-ER Capsules and CYP2D6 inhibitors may increase the exposure of MAS-ER Capsules compared to the use of the drug alone and increase the risk of serotonin syndrome. |
| Intervention | Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during MAS-ER Capsules initiation and after a dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the CYP2D6 inhibitor |
| Examples | paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir |
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| Clinical Impact | Increase blood levels and potentiate the action of amphetamine. |
| Intervention | Co-administration of MAS-ER Capsules and gastrointestinal or urinary alkalinizing agents should be avoided. |
| Examples | Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g. acetazolamide, some thiazides). |
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| Clinical Impact | Lower blood levels and efficacy of amphetamines. |
| Intervention | Increase dose based on clinical response. |
| Examples | Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid). Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts). |
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| Clinical Impact | May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated. |
| Intervention | Monitor frequently and adjust or use alternative therapy based on clinical response. |
| Examples | desipramine, protriptyline |
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| Clinical Impact | Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone. |
| Intervention | Monitor patients for changes in clinical effect and adjust therapy based on clinical response. |
| Examples | omeprazole |
| % Change from Plavix (300 mg/75 mg) alone | ||||||
| Plavix plus | Cmax (ng/mL) | AUC | Platelet Inhibition |
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| Day 1 | Day 5 | Day 1 | Day 5 |
Day 1 | Day 5 | |
| Omeprazole |
↓46% | ↓42% | ↓45% | ↓40% | ↓39% | ↓21% |
| Pantoprazole 80 mg | ↓24% | ↓28% | ↓20% | ↓14% | ↓15% | ↓11% |
| Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. | |
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| Beta-adrenergic antagonists
(e.g., Propranolol > 160 mg/day) |
In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state. |
| Glucocorticoids
(e.g., Dexamethasone |
Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above). |
| Other drugs:
Amiodarone |
Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients. |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Drug | Description |
| Corticosteroids | Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism |
| Ammonium Sulfate | Increases plasma salicylate level |
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| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – antagonist: maraviroc | ↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
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| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin receptor antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA. |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Long-acting beta-adrenoceptor agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
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The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone
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With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage
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| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
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The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone
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With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage
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| Antihypertensive Drugs
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Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
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Monitor blood pressure and adjust dose accordingly
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| Benzodiazepines (e.g., lorazepam)
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The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone
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Monitor sedation and blood pressure. Adjust dose accordingly.
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| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate |
| Drugs Known to Prolong QT Interval |
Avoid Use | Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin. |
| Cyclosporine | Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine. |
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin |
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised. |
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil | Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine | Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
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| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Probenecid | Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
| * Antacids may affect absorption of phenytoin. † The induction potency of St. John's wort may vary widely based on preparation. |
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| Specific Drugs Reported | |||
|---|---|---|---|
| also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
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| acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide |
diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine |
lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone |
propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton |
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Concentration of Lamotrigine or Concomitant Drug |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
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Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide |
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Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
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Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| *Change relative to reference
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Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Recommendation |
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Inhibitors |
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daily |
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PgP inducers) |
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Do not exceed twice the patient’s usual dose |
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Inhibitors |
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needed |
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needed |
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daily |
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needed |
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needed |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*) | Risperidone Dose Recommendation | ||
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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Monitor patients with concomitant use of CAMBIA with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ |
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Concomitant use of CAMBIA and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of CAMBIA with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of CAMBIA and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of CAMBIA and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of CAMBIA and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of CAMBIA and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of CAMBIA and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ |
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The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended. |
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Concomitant use of CAMBIA and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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Diclofenac is metabolized predominantly by Cytochrome P-450 CYP2C9. Co- administration of medications that inhibit CYP2C9 may affect the pharmacokinetics of diclofenac [ |
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During concomitant use of CAMBIA and drugs that inhibit CYP2C9, an increase in the duration between CAMBIA doses for subsequent migraine attacks may be necessary. |
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
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| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitors (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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or Concomitant Drug |
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| Atazanavir/Ritonavir | ↓ Atazanavir ↑ Nevirapine |
Do not coadminister nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. |
| Clarithromycin | ↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Efavirenz | ↓ Efavirenz | There has been no determination of appropriate doses for the safe and effective use of this combination [ |
| Ethinyl estradiol and Norethindrone |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Fluconazole | ↑ Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration and patients should be monitored closely for nevirapine-associated adverse events. |
| Fosamprenavir | ↓ Amprenavir ↑ Nevirapine |
Coadministration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir | ↓ Amprenavir ↑ Nevirapine |
No dosing adjustments are required when nevirapine is coadministered with 700 mg/100 mg of fosamprenavir/ritonavir twice daily. |
| Indinavir | ↓ Indinavir | Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. |
| Ketoconazole | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Lopinavir/Ritonavir | ↓ Lopinavir |
A dose increase of lopinavir/ritonavir oral solution to 533 mg/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 kg to < 15 kg; 11/2.75 mg/kg for those 15 kg to 45 kg; up to a maximum dose of 533 mg/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine. |
| Methadone | ↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
| Nelfinavir | ↓ Nelfinavir M8 Metabolite ↓ Nelfinavir Cmin |
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. |
| Rifabutin | ↑ Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
| Saquinavir/Ritonavir | The interaction between nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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| Antiarrhythmics | Amiodarone, disopyramide, lidocaine | Plasma concentrations may be decreased. |
| Anticonvulsants | Carbamazepine, clonazepam, ethosuximide | Plasma concentrations may be decreased. |
| Antifungals | Itraconazole | Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. |
| Calcium channel blockers | Diltiazem, nifedipine, verapamil | Plasma concentrations may be decreased. |
| Cancer chemotherapy | Cyclophosphamide | Plasma concentrations may be decreased. |
| Ergot alkaloids | Ergotamine | Plasma concentrations may be decreased. |
| Immunosuppressants | Cyclosporin, tacrolimus, sirolimus | Plasma concentrations may be decreased. |
| Motility agents | Cisapride | Plasma concentrations may be decreased. |
| Opiate agonists | Fentanyl | Plasma concentrations may be decreased. |
| Antithrombotics | Warfarin | Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
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| Anticoagulants
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argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
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| Antiplatelet Agents
|
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
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| Nonsteroidal Anti-Inflammatory Agents
|
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
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| Serotonin Reuptake Inhibitors
|
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone
|
| ↓= Decreased (induces lamotrigine glucuronidation). | ||
| ↑= Increased (inhibits lamotrigine glucuronidation). | ||
| ? = Conflicting data. | ||
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Specific Drugs |
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a For magnitude of interactions see |
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b See |
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| c In combination with atazanavir 300 mg and ritonavir 100 mg once daily. | ||
| d In combination with atazanavir 400 mg once daily. | ||
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didanosine buffered formulations enteric-coated (EC) capsules |
↓ atazanavir ↓ didanosine |
Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times. |
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↓ atazanavir ↑ tenofovir |
Tenofovir may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). |
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↓ atazanavir | Efavirenz decreases atazanavir exposure. If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure. |
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↓ atazanavir ↑ nevirapine |
Do not coadminister REYATAZ with
nevirapine because:
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↑ saquinavir | Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see |
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↑ atazanavir | If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for NORVIR® (ritonavir) for information on drug interactions with ritonavir. |
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↑ other protease inhibitor |
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↓ atazanavir | Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications. |
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↑ amiodarone, bepridil, lidocaine (systemic), quinidine | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate). |
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↑ warfarin | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored. |
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↑ tricyclic antidepressants | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ. |
| trazodone | ↑ trazodone | Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered. |
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↑ ketoconazole ↑ itraconazole |
Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir. |
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Effect is unknown | Coadministration of voriconazole with REYATAZ, with or without ritonavir, has not been studied. Administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%. Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Coadministration of voriconazole with REYATAZ (without ritonavir) may increase atazanavir concentrations; however, no data are available. |
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↑ colchicine | REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment. Treatment of gout flares:
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↑ rifabutin | A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted. |
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↑ midazolam | Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED. |
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↑ diltiazem and desacetyl-diltiazem | Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied. |
| eg, felodipine, nifedipine, nicardipine, and verapamil | ↑ calcium channel blocker | Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. |
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↓ atazanavir ↑ bosentan |
Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended.
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↑ atorvastatin ↑ rosuvastatin |
Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with REYATAZ (with or without ritonavir). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs. |
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↓ atazanavir | Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance. |
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REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist. An H2-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women. |
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Whenever an H2-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
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↓ ethinyl estradiol ↑ norgestimatec ↑ ethinyl estradiol ↑ norethindroned |
Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least
35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. |
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↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate). |
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↑ salmeterol | Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
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Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
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Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see |
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↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir |
Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to |
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↑ buprenorphine ↑ norbuprenorphine |
Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine. |
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↑ sildenafil ↑ tadalafil ↑ vardenafil |
Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
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↓ atazanavir | Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance. |
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The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose. |
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Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ. |
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| Tizanidine |
Contraindicated |
Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline |
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate |
| Drugs Known to Prolong QT Interval |
Avoid Use |
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs |
Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin |
Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine |
Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs |
Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate |
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole |
Use with caution |
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin |
| Clozapine |
Use with caution |
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs |
Use with caution |
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil |
Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine |
Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
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| Probenecid |
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
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| atazanavir | ↑ | Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| atazanavir/ritonavir | ↑ | Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| efavirenz | ↓ | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| etravirine | ↓ | Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| tipranavir/ritonavir | ↓ | Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended. |
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| omeprazole | ↑ | Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| rifampin | ↓ | Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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| Known CYP2D6 Poor Metabolizers | Administer half of usual dose |
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors | Administer a quarter of usual dose |
| Strong CYP2D6 |
Administer half of usual dose |
| Strong CYP2D6 |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
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| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
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Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T 4 and T 3 levels and increase TSH, although all values remain within normal limits in most patients. |
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Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT 4 . Continued administration results in a decrease in serum T 4 and normal FT 4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T 4 and T 3 to TBG and transthyretin. An initial increase in serum FT 4 is followed by return of FT 4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T 4 levels may decrease by as much as 30%. |
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Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T 4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T 4 to T 3, leading to decreased T 3 levels. However, serum T 4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T 3 and T 4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T 3 concentrations by 30% with minimal change in serum T 4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T 3 and T 4 levels due to decreased TBG production (see above). |
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- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| Drug/Drug Class (Mechanism of Interaction by Voriconazole) |
Drug Plasma Exposure (Cmax and AUCτ) | Recommendations for Drug Dosage Adjustment/Comments |
|---|---|---|
| Sirolimus (CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (400 mg q24h) (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (300 mg q24h) (CYP3A4 Inhibition) |
Slight Increase in AUCτ | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) Low-dose Ritonavir (100 mg q12h) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ
Slight Decrease in Ritonavir Cmax and AUCτ |
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
|
| Cyclosporine (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) |
Increased | Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary |
| Oxycodone (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary |
| NSAIDs (CYP2C9 Inhibition) |
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed |
| Tacrolimus (CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin (CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole (CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
No dosage adjustment for indinavir when coadministered with voriconazole Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors |
| Other NNRTIs (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
| Everolimus (CYP3A4 Inhibition) |
Not Studied |
Concomitant administration of voriconazole and everolimus is not recommended. |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1) |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2) |
| Antidiabetic agents | Carefully monitor blood glucose (5.11, 7.3) |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding |
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone |
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Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. |
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis |
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During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy |
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. |
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Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin
|
NC or 25% increase
|
48% decrease
|
| Carbamazepine (CBZ)
|
NC
|
40% decrease
|
| CBZ epoxide
|
NC
|
NE
|
| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
|
NE
|
| Primidone
|
NC
|
NE
|
| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
|
| edema hereditary coumarin resistance hyperlipemia |
hypothyroidism nephrotic syndrome |
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atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
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fibrates, gemfibrozil |
||
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digoxin |
|
| Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours | Simultaneous dosing of Vardenafil and Alpha-Blocker | ||||
| Alpha-Blocker | Vardenafil 10 mg Placebo-Subtracted |
Vardenafil 20 mg Placebo-Subtracted |
Vardenafil 10 mg Placebo-Subtracted |
Vardenafil 20 mg Placebo-Subtracted |
|
| Terazosin 10 mg daily |
Standing SBP | -7 (-10, -3) | -11 (-14, -7) | -23 (-31, 16) |
-14 (-33, 11) |
| Supine SBP | -5 (-8, -2) | -7 (-11, -4) | -7 (-25, 19) |
-7 (-31, 22) |
|
| Tamsulosin 0.4 mg daily |
Standing SBP | -4 (-8, -1) | -8 (-11, -4) | -8 (-14, -2) | -8 (-14, -1) |
| Supine SBP | -4 (-8, 0) | -7 (-11, -3) | -5 (-9, -2) | -3 (-7, 0) | |
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| Antiarrhythmics:
Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin |
Not Recommended Use With Caution |
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
|
| Oral Anticoagulants:
Warfarin |
Use With Caution |
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| Antiepileptics:
Carbamazepine |
Use With Caution |
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| Antifungals:
Itraconazole Fluconazole |
Use With Caution No Dose Adjustment |
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| Anti-Gout Agents:
Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function) |
Contraindicated Use With Caution |
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| Antipsychotics:
Pimozide Quetiapine |
Contraindicated |
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| Antispasmodics:
Tolterodine (patients deficient in CYP2D6 activity) |
Use With Caution |
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| Antivirals:
Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine |
Use With Caution No Dose Adjustment |
Maraviroc Zidovudine: |
|
| Calcium Channel Blockers:
Verapamil Amlodipine Diltiazem Nifedipine |
Use With Caution |
|
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| Ergot Alkaloids:
Ergotamine Dihydroergotamine |
Contraindicated |
|
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| Gastroprokinetic Agents:
Cisapride |
Contraindicated |
|
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| HMG-CoA Reductase Inhibitors:
Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin |
Contraindicated Use With Caution No Dose Adjustment |
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| Hypoglycemic Agents:
Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin |
Use With Caution |
|
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| Immunosuppressants:
Cyclosporine Tacrolimus |
Use With Caution |
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| Phosphodiesterase inhibitors:
Sildenafil Tadalafil Vardenafil |
Use With Caution |
|
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| Proton Pump Inhibitors:
Omeprazole |
No Dose Adjustment |
|
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| Xanthine Derivatives:
Theophylline |
Use With Caution |
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| Triazolobenzodiazepines and Other Related Benzodiazepines:
Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam |
Use With Caution No Dose Adjustment |
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
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| Cytochrome P450 Inducers:
Rifabutin |
Use With Caution |
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| Other Drugs
Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution |
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. |
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| Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
Hexobarbital Phenytoin Valproate |
Use With Caution |
There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate. |
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Drugs that Affect Clarithromycin |
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Recommendation |
Comments |
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| Antifungals:
Itraconazole |
Use With Caution |
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| Antivirals:
Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function) |
Use With Caution No Dose Adjustment |
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. |
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| Proton Pump Inhibitors:
Omeprazole |
Use With Caution |
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| Miscellaneous Cytochrome P450 Inducers:
Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine |
Use With Caution |
Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above). |
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| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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See |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) | The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone
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With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage
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| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) | The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone
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With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage
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| Antihypertensive Drugs | Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. | Monitor blood pressure and adjust dose accordingly
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| Benzodiazepines(e.g., lorazepam) | The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone
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Monitor sedation and blood pressure. Adjust dose accordingly. |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
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48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
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NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel |
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See the prescribing information for other drugs dependent on gastric pH for absorption. |
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See |
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| Estrogen-containing oral contraceptivepreparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
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and carbamazepine epoxide |
? carbamazepine epoxide |
May increase carbamazepine epoxide levels. |
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| Valproate | ↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| |
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| NA – Not available/reported | |||
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Concentration Increase |
Increase |
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diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole, |
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cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine |
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were studied but reported no significant changes on digoxin exposure. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Hepatitis C Protease inhibitor (boceprevir) | |
| AED Co-administered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increasea | 48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxideb | NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
|
a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated |
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| Interacting Agents | Prescribing Recommendations |
|---|---|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
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| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ |
||
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. |
||
| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
||
| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated | Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions ( |
||
| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) | To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. | ||
| Cyclosporine | Use with caution (transient elevations in serum creatinine) | Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. | ||
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) | The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). | ||
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels | Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. | ||
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see |
||
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. | ||
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. | ||
| Sildenafil | Use with caution Two-fold increase in exposure | Monitor for sildenafil toxicity (see |
||
| Duloxetine | Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity | ||
| Caffeine/Xanthine Derivatives | Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life | Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. | ||
|
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||||
| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
||
| Probenecid |
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
||
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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Avoid atorvastatin
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| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary | |
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Do not exceed 20 mg atorvastatin daily
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| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily | |
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| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| CYP2C9
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amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
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aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
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| CYP1A2
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acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
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montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
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| CYP3A4
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alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
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armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide
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| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| Estrogen-containing oral
contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine
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Decreased lamotrigine levels
approximately 50%. |
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↓ levonorgestrel
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Decrease in levonorgestrel component by 19%.
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| Carbamazepine (CBZ) and
CBZ epoxide |
↓ lamotrigine
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Addition of carbamazepine decreases lamotrigine
concentration approximately 40%. |
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? CBZ epoxide
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May increase CBZ epoxide levels
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| Phenobarbital/Primidone
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↓ lamotrigine
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Decreased lamotrigine
concentration approximately 40%. |
| Phenytoin (PHT)
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↓ lamotrigine
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Decreased lamotrigine
concentration approximately 40% |
| Rifampin
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↓ lamotrigine
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Decreased lamotrigine AUC
approximately 40% |
| Valproate
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↑ lamotrigine
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Increased lamotrigine concentrations slightly
more than 2-fold. |
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? valproate
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Decreased valproate concentrations an average of
25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Tizanidine |
Contraindicated |
Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see CONTRAINDICATIONS ( |
| Theophylline |
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see WARNINGS AND PRECAUTIONS ( |
| Drugs Known to Prolong QT Interval |
Avoid Use |
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see WARNINGS AND PRECAUTIONS ( |
| Oral antidiabetic drugs |
Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see ADVERSE REACTIONS ( |
| Phenytoin |
Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine |
Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs |
Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate |
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole |
Use with caution |
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co- administration with ciprofloxacin [see WARNINGS AND PRECAUTIONS ( |
| Clozapine |
Use with caution |
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs |
Use with caution |
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil |
Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity [see CLINICAL PHARMACOLOGY |
| Duloxetine |
Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
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| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation- containing products administration [see DOSAGE AND ADMINISTRATION ( |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Probenecid |
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
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Phenytoin Phenobarbital St. John’s wort ( |
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Sucralfate Buffered medications |
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The concomitant use of tramadol hydrochloride and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression |
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If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation. |
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Quinidine, fluoxetine, paroxetine and bupropion | |
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The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) | |
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The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase |
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If concomitant use is necessary, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride, acetaminophen and carbamazepine is not recommended. |
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Rifampin, carbamazepine, phenytoin | |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. | |
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Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. | |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. | |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride and acetaminophen if serotonin syndrome is suspected. | |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). | |
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MAOI interactions with opioids may manifest as serotonin syndrome |
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Do not use tramadol hydrochloride and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment. | |
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phenelzine, tranylcypromine, linezolid | |
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May reduce the analgesic effect of tramadol hydrochloride and acetaminophen and/or precipitate withdrawal symptoms. | |
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Avoid concomitant use. | |
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butorphanol, nalbuphine, pentazocine, buprenorphine | |
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Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. | |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride and acetaminophen and/or the muscle relaxant as necessary. | |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. | |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. | |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. | |
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Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride and acetaminophen is used concomitantly with anticholinergic drugs. | |
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Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity. | |
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Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed. | |
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Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times. | |
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Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed. | |
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| nafcillin | carbamazepine | bosentan |
| rifampin | oxcarbazepine | octreotide |
| phenobarbital | orlistat | |
| phenytoin | sulfinpyrazone | |
| St. John's Wort | ||
| terbinafine | ||
| ticlopidine |
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine
|
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
|
| Warfarin
|
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (
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| Antidiabetic agents
|
Carefully monitor blood glucose (
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide
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Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide
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Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents)
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Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
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Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
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Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin
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Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)
|
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone
|
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage
|
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)
|
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone
|
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage
|
| Antihypertensive Drugs
|
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.
|
Monitor blood pressure and adjust dose accordingly
|
| Benzodiazepines (e.g., lorazepam)
|
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone
|
Monitor sedation and blood pressure. Adjust dose accordingly.
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|
The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome. |
|
|
Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue |
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selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue |
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Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias. |
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Concomitant use of pimozide and sertraline hydrochloride is contraindicated |
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The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome. |
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Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs |
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other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort |
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The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding. |
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Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio |
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aspirin, clopidogrel, heparin, warfarin |
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Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma |
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Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted. |
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warfarin |
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Sertraline hydrochloride is a CYP2D6 inhibitor |
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Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued. |
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propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine |
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Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations. |
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Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed. |
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phenytoin, fosphenytoin |
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Concentration of Lamotrigine or Concomitant Drug |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| ↑ Indicates increase. ↓ Indicates decrease. |
||
| Drug | Effect | Clinical Comment |
| ganciclovir | ↑didanosine concentration | If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-associated toxicity. |
| methadone | ↓didanosine concentration | If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. |
| nelfinavir | No interaction 1 hour after didanosine | Administer nelfinavir 1 hour after didanosine delayed-release capsules. |
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↑didanosine concentration |
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Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
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Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
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Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
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NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
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During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
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During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [
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During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
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During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
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Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
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During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
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Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
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Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
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During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
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| Grapefruit juice | Avoid grapefruit juice |
| AED Coadministered | AED Concentration | Topiramate Concentration |
|---|---|---|
| Phenytoin |
NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxide |
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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| Adrenal Cortical Steroid Inhibitors | Antipsychotic Medications | Hypolipidemics† |
| Antacids | Antithyroid Drugs† | Bile Acid-Binding Resins† |
| Antianxiety Agents Antiarrhythmics† |
Barbiturates Diuretics† |
HMG-CoA Reductase Inhibitors† |
| Anticonvulsants† | Enteral Nutritional Supplements | Immunosuppressives |
| Antidepressants† | Fungal Medications, Systemic† | Oral Contraceptives, |
| Antihistamines | Gastric Acidity and Peptic Ulcer Agents† | Estrogen Containing |
| Antineoplastics† | Hypnotics† | Selective Estrogen Receptor Modulators |
| Steroids, Adrenocortical† | ||
| Tuberculosis Agents†
Vitamins† |
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| alcohol |
warfarin sodium underdosage | phenytoin |
| aminoglutethimide | cyclophosphamide |
pravastatin |
| amobarbital | dicloxacillin | prednisone |
| atorvastatin |
ethchlorvynol | primidone |
| azathioprine | glutethimide | propylthiouracil |
| butabarbital | griseofulvin | raloxifene |
| butalbital | haloperidol | ranitidine |
| carbamazepine | meprobamate | rifampin |
| chloral hydrate |
6-mercaptopurine | secobarbital |
| chlordiazepoxide | methimazole |
spironolactone |
| chlorthalidone | moricizine hydrochloride |
sucralfate |
| cholestyramine |
nafcillin | trazodone |
| clozapine | paraldehyde | vitamin C (high dose) |
| corticotropin | pentobarbital | vitamin K |
| cortisone | phenobarbital | |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Drug | Description |
|---|---|
| Heparin | Salicylate decreases platelet adhesivesness and interferes with hemostasis in heparin-treated patients |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia |
| Uricosuric Agents | Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited |
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| ↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
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150 mcg levonorgestrel |
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
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? carbamazepine epoxide |
May increase carbamazepine epoxide levels. |
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? valproate |
There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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See prescribing information for voriconazole. |
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The concomitant use of Sufentanil Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of sufentanil, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Sufentanil Citrate Injection is achieved After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease |
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If concomitant use is necessary, consider dosage reduction of Sufentanil Citrate Injection until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. |
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Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice |
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The concomitant use of Sufentanil Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of sufentanil After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase |
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If concomitant use is necessary, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Sufentanil Citrate Injection dosage reduction and monitor for signs of respiratory depression. |
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Rifampin, carbamazepine, phenytoin |
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The concomitant use of Sufentanil Citrate Injection with CNS depressants my result in decreased pulmonary artery pressure and may cause hypotension. Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Sufentanil Citrate Injection. As postoperative analgesia, concomitant use of Sufentanil Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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As postoperative analgesia, start with a lower dose of Sufentanil Citrate Injection and monitor patients for signs of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available. |
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Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Sufentanil Citrate Injection if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) |
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The use of Sufentanil Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of Sufentanil Citrate Injection and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Sufentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Sufentanil Citrate Injection and/or the muscle relaxant as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when Sufentanil Citrate Injection is used concomitantly with anticholinergic drugs. |
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Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Sufentanil Citrate Injection. |
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Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected. |
| ↑ Indicates increase. | ||
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| Drugs that may cause pancreatic toxicity | ↑risk of pancreatitis | Use only with extreme caution. |
| Neurotoxic drugs | ↑risk of neuropathy | Use with caution. |
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| Atazanavir/Ritonavir* | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* | ↓Amprenavir ↑Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir* | ↓Amprenavir ↑Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* | ↓ Indinavir | The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* | ↓Lopinavir | Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir | The interaction between nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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||
| Efavirenz* | ↓ Efavirenz |
The appropriate doses of these combinations with respect to safety and efficacy have not been established. |
|
Delavirdine Etravirine Rilpivirine |
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
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|
Methadone* |
↓ Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Clarithromycin* |
↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Rifabutin* |
↑Rifabutin |
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin* |
↓ Nevirapine |
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* |
↑Nevirapine |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Ketoconazole* |
↓ Ketoconazole |
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Itraconazole |
↓ Itraconazole |
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be decreased. | Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be increased. | Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Concomitant Drug Class: Drug Name | Effect | Clinical Comment |
|---|---|---|
|
|
||
| Protease inhibitor: atazanavir |
↓atazanavir ↑ tenofovir |
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. |
| Protease inhibitor: fosamprenavir calcium |
↓ amprenavir | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: indinavir |
↓ indinavir | The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Protease inhibitor: lopinavir/ritonavir |
↓ lopinavir ↑ tenofovir |
Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions. |
| Protease inhibitor: ritonavir |
↑ ritonavir ↑ efavirenz |
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. |
| Protease inhibitor: saquinavir |
↓ saquinavir | Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
| CCR5 co-receptor antagonist: maraviroc |
↓ maraviroc | Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA. |
| NRTI: didanosine |
↑ didanosine | Coadministration of ATRIPLA and didanosine should be undertaken with caution, and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information. |
| NNRTI: Other NNRTIs |
↑ or ↓ efavirenz and/or NNRTI | Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs. |
| Integrase strand transfer inhibitor: raltegravir |
↓ raltegravir | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
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| Protease inhibitor: boceprevir |
↓ boceprevir | Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided. |
| Protease inhibitor: simeprevir |
↓ simeprevir ↔ efavirenz |
Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir. |
| NS5A inhibitors/NS5B polymerase inhibitors: ledipasvir/sofosbuvir |
↑ tenofovir | Patients receiving ATRIPLA and HARVONI® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF. |
| sofosbuvir/velpatasvir | ↑ tenofovir ↓ velpatasvir |
Coadministration of efavirenz-containing regimens and EPCLUSA® (sofosbuvir/velpatasvir) is not recommended. |
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||
| Anticoagulant: warfarin |
↑ or ↓ warfarin | Plasma concentrations and effects potentially increased or decreased by efavirenz. |
| Anticonvulsants: carbamazepine |
↓ carbamazepine ↓ efavirenz |
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. |
| phenytoin phenobarbital |
↓ anticonvulsant ↓ efavirenz |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants: bupropion |
↓ buproprion | The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| sertraline | ↓ sertraline | Increases in sertraline dose should be guided by clinical response. |
| Antifungals: itraconazole |
↓ itraconazole ↓ hydroxy-itraconazole |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| ketoconazole | ↓ ketoconazole | Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. |
| posaconazole | ↓ posaconazole | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective: clarithromycin |
↓ clarithromycin ↑ 14-OH metabolite |
Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation. |
| Antimycobacterial: rifabutin |
↓ rifabutin | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| rifampin | ↓ efavirenz | If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended. |
| Antimalarials: artemether/lumefantrine |
↓ artemether ↓ dihydroartemisinin ↓ lumefantrine |
Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation. |
| atovaquone/proguanil | ↓ atovaquone ↓ proguanil |
Concomitant administration of atovaquone/proguanil with ATRIPLA is not recommended. |
| Calcium channel blockers: diltiazem |
↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. |
| Others (e.g., felodipine, nicardipine, nifedipine, verapamil) | ↓ calcium channel blocker | No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin |
↓ atorvastatin ↓ pravastatin ↓ simvastatin |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: Oral: ethinyl estradiol/norgestimate |
↓ active metabolites of norgestimate | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant: etonogestrel |
↓ etonogestrel | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immuno-suppressant | Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. |
| Narcotic analgesic: methadone |
↓ methadone | Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
| Drug or Drug Class | Effect |
|---|---|
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| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Coadministered Drug
|
Dosing Schedule
|
|
Effect on Active
Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose
Recommendation |
|
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Coadministered Drug
|
Risperidone
|
AUC
|
C
m
a
x
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|
| Enzyme (CYP2D6)
Inhibitors |
|
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| Fluoxetine
|
20 mg/day
|
2 or 3 mg twice
daily |
1.4
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1.5
|
Re-evaluate dosing. Do not exceed 8 mg/day
|
| Paroxetine
|
10 mg/day
|
4 mg/day
|
1.3
|
-
|
Re-evaluate dosing.
|
|
|
20 mg/day
|
4 mg/day
|
1.6
|
-
|
Do not exceed 8 mg/day
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|
40 mg/day
|
4 mg/day
|
1.8
|
-
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|
| Enzyme (CYP3A/
PgP inducers) |
|
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|
|
| Carbamazepine
|
573 ± 168 mg/day
|
3 mg twice daily
|
0.51
|
0.55
|
Titrate dose upwards.
Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)
Inhibitors |
|
|
|
|
|
| Ranitidine
|
150 mg twice daily
|
1 mg single dose
|
1.2
|
1.4
|
Dose adjustment not
needed |
| Cimetidine
|
400 mg twice daily
|
1 mg single dose
|
1.1
|
1.3
|
Dose adjustment not
needed |
| Erythromycin
|
500 mg four times
daily |
1 mg single dose
|
1.1
|
0.94
|
Dose adjustment not
needed |
| Other Drugs
|
|
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|
| Amitriptyline
|
50 mg twice daily
|
3 mg twice daily
|
1.2
|
1.1
|
Dose adjustment not
needed |
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| Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). |
Quinine sulfate prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use ( |
| Other antimalarials (e.g., halofantrine, mefloquine). |
ECG abnormalities including QT prolongation Avoid concomitant use ( |
| CYP3A4 inducers or inhibitors |
Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( |
| CYP3A4 and CYP2D6 substrates |
Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( |
| Digoxin |
Increased digoxin plasma concentration ( |
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|---|---|
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Hepatitis C protease inhibitor (boceprevir) |
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| Strong CYP3A4 inhibitors (e.g., |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily* |
| Grapefruit juice | Avoid grapefruit juice |
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| Tizanidine |
Contraindicated |
Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline |
Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. |
| Drugs Known to Prolong QT Interval |
Avoid Use |
Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs |
Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin |
Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine |
Use with caution (transient elevations in serum creatinine) |
Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs |
Use with caution (Increase in anticoagulant effect) |
The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate |
Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole |
Use with caution |
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin |
| Clozapine |
Use with caution |
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs |
Use with caution |
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing. |
| Sildenafil |
Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine |
Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives |
Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life |
Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
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| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) |
Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Probenecid |
Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) |
Potentiation of ciprofloxacin toxicity may occur. |
| DRUG | DESCRIPTION OF INTERACTION |
|
|
|
| Pyrazinamide | Inhibits pyrazinamide induced hyperuricemia. |
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. |
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|---|---|
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including antacids, metal cations or didanosine |
formulation is taken within 2 hours of this product. |
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INR, watch for bleeding |
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
| AED Coadministered | Dose of AED (mg/day) | Oxcarbazepine Dose (mg/day) | Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) | Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine |
400 to 2000 |
900 |
nc |
40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital |
100 to 150 |
600 to 1800 |
14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin |
250 to 500 |
600 to 1800 >1200 to 2400 |
nc up to 40% increase |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid |
400 to 2800 |
600 to 1800 |
nc |
18% decrease [CI: 13% decrease, 40% decrease] |
|
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|---|---|---|
| ↓ = Decreased (induces lamotrigine glucuronidation) |
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| ↑ = Increased (inhibits lamotrigine glucuronidation) |
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| ? = Conflicting data |
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Hepatitis C protease inhibitor (boceprevir) |
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| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine |
Decreased lamotrigine levels approximately 50%. |
| |
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| |
? CBZ epoxide |
May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine |
Increased lamotrigine concentrations slightly more than 2-fold. |
| |
? valproate |
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Known CYP2D6 Poor Metabolizers
|
Administer half of usual dose
|
| Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors
|
Administer a quarter of usual dose
|
| Strong CYP2D6 or CYP3A4 inhibitors
|
Administer half of usual dose
|
| Strong CYP2D6 and CYP3A4
inhibitors |
Administer a quarter of usual dose
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| Strong CYP3A4 inducers
|
Double usual dose over 1 to 2 weeks
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| Strong CYP2D6 |
Administer half of usual dose |
| Strong CYP2D6 |
Administer a quarter of usual dose |
| Strong CYP3A4 inducers | Double usual dose over 1 to 2 weeks |
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| Phenytoin
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NC or 25% increase
a
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48% decrease
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| Carbamazepine (CBZ)
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NC
|
40% decrease
|
| CBZ epoxide
b
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NC
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NE
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| Valproic acid
|
11% decrease
|
14% decrease
|
| Phenobarbital
|
NC
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NE
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| Primidone
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NC
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NE
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| Lamotrigine
|
NC at TPM doses up to 400 mg/day
|
13% decrease
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|
(mg/day) |
(mg/day) |
Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400-2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
|
Renal Function |
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Function |
angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin. |
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Analog |
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Agents |
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and calcium channel blockers |
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| Interacting Drug | Interaction |
|---|---|
| Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). | Quinine sulfate capsules, USP prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use ( |
| Other antimalarials (e.g., halofantrine, mefloquine). | ECG abnormalities including QT prolongation. Avoid concomitant use ( |
| CYP3A4 inducers or inhibitors | Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( |
| CYP3A4 and CYP2D6 substrates | Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( |
| Digoxin | Increased digoxin plasma concentration ( |
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| Concomitant Drug Name or Drug Class | Clinical Rationale | Clinical Recommendation |
|---|---|---|
| Monoamine Oxidase Inhibitors (MAOIs) | Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure. | Do not administer VYVANSE concomitantly or within 14 days after discontinuing MAOI treatment |
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The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
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Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue
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selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
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Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
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Concomitant use of pimozide and sertraline hydrochloride is contraindicated
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The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
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Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs
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other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
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The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
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Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio
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aspirin, clopidogrel, heparin, warfarin
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Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma
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Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
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warfarin
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Sertraline hydrochloride is a CYP2D6 inhibitor
|
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Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
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propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
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Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
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Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
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phenytoin, fosphenytoin
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
|
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
|
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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- Interferon-α - Interleukin-2 |
|
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
|
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidibetic agents |
Carefully monitor blood glucose ( |
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| Concomitant Drug Class: Drug Name | Effect on Concentration of Amprenavir or Concomitant Drug | Clinical Comment |
|
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|
Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
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Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
|
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|
An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
|
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|
Appropriate doses of the combination with respect to safety and efficacy have not been established. |
|
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||
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|
Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics. |
|
|
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
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↑Rifabutin and rifabutin metabolite |
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↑Benzodiazepines | Clinical significance is unknown. A decrease in benzodiazepine dose may be needed. |
|
|
↑Calcium channel blockers | Use with caution. Clinical monitoring of patients is recommended. |
|
|
↓Amprenavir | Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations. |
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|
Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations. |
|
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|
Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin or pravastatin. |
|
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↑Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents. |
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↓Methadone | Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms. |
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Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations. |
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↑Tricyclics | Therapeutic concentration monitoring is recommended for tricyclic antidepressants. |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
|
|
Reserve concomitant prescribing
of these drugs for use in patients for whom alternative treatment
options are inadequate. Limit dosages and durations to the minimum
required. Follow patients closely for signs of respiratory depression
and sedation |
|
|
Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome |
|
|
If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DILAUDID INJECTION and DILAUDID-HP INJECTION if serotonin syndrome is suspected. |
|
|
Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids
may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory
depression, coma) If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. |
|
|
The use of DILAUDID INJECTION or DILAUDID-HP INJECTION is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. |
|
|
phenelzine, tranylcypromine, linezolid |
|
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|
|
May reduce the analgesic effect of DILAUDID INJECTION and DILAUDID-HP INJECTION and/or precipitate withdrawal syndrome. |
|
|
Avoid concomitant use. |
|
|
butorphanol, nalbuphine, pentazocine, buprenorphine |
|
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|
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Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
|
|
Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DILAUDID INJECTION and DILAUDID-HP INJECTION and/or the muscle relaxant as necessary. |
|
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|
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
|
|
Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
|
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|
|
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
|
|
Monitor patients for signs of urinary retention or reduced gastric motility when DILAUDID INJECTION and DILAUDID-HP INJECTION are used concomitantly with anticholinergic drugs. |
|
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||
| Clinical Impact: | Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. | |
| Intervention: | Monitor patients with concomitant use of naproxen sodium tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see
|
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|
||
| Clinical Impact: | Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see
|
|
| Intervention: | Concomitant use of naproxen sodium tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see
|
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|
||
| Clinical Impact: | NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. | |
| Intervention: | During concomitant use of naproxen sodium tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen sodium tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see
|
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|
||
| Clinical Impact: | Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. | |
| Intervention | During concomitant use of naproxen sodium tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see
|
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|
||
| Clinical Impact: | The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. | |
| Intervention: | During concomitant use of naproxen sodium tablets and digoxin, monitor serum digoxin levels. | |
|
|
||
| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. | |
| Intervention: | During concomitant use of naproxen sodium tablets and lithium, monitor patients for signs of lithium toxicity. | |
|
|
||
| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). | |
| Intervention: | During concomitant use of naproxen sodium tablets and methotrexate, monitor patients for methotrexate toxicity. | |
|
|
||
| Clinical Impact: | Concomitant use of naproxen sodium tablets and cyclosporine may increase cyclosporine’s nephrotoxicity. | |
| Intervention: | During concomitant use of naproxen sodium tablets and cyclosporine, monitor patients for signs of worsening renal function. | |
|
|
||
| Clinical Impact: | Concomitant use of naproxen sodium tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see
|
|
| Intervention: | The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. | |
|
|
||
| Clinical Impact: | Concomitant use of naproxen sodium tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). | |
| Intervention: | During concomitant use of naproxen sodium tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. | |
|
|
||
| Clinical Impact: | Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. | |
| Intervention: | Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen sodium tablets are not recommended. Due to the gastric pH elevating effects of H 2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed-release tablets are not recommended. | |
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||
| Clinical Impact: | Concomitant administration of cholestyramine can delay the absorption of naproxen. | |
| Intervention: | Concomitant administration of cholestyramine with naproxen sodium tablets is not recommended. | |
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||
| Clinical Impact: | Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. | |
| Intervention: | Patients simultaneously receiving naproxen sodium tablets and probenecid should be observed for adjustment of dose if required. | |
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||
| Clinical Impact: | Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. | |
| Intervention: | Patients simultaneously receiving naproxen sodium tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. | |
| Concomitant Drug Name or Drug Class | Clinical Rationale and Magnitude of Drug Interaction | Clinical Recommendation |
| Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure |
Consider dose reduction
|
| Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz | Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 60% decrease in exposure | Consider dose increase |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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|
See prescribing information for voriconazole. |
| Drugs That are Affected by Ciprofloxacin | ||
|---|---|---|
| Drug(s) | Recommendation | Comments |
| Tizanidine | Contraindicated | Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine |
| Theophylline | Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) |
Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate |
| Drugs Known to Prolong QT Interval | Avoid Use | Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) |
| Oral antidiabetic drugs | Use with caution Glucose-lowering effect potentiated |
Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported |
| Phenytoin | Use with caution Altered serum levels of phenytoin (increased and decreased) |
To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin. |
| Cyclosporine | Use with caution (transient elevations in serum creatinine) | Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. |
| Anti-coagulant drugs | Use with caution (Increase in anticoagulant effect) | The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin). |
| Methotrexate | Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels |
Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated. |
| Ropinirole | Use with caution | Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin |
| Clozapine | Use with caution | Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. |
| NSAIDs | Use with caution | Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing. |
| Sildenafil | Use with caution Two-fold increase in exposure |
Monitor for sildenafil toxicity |
| Duloxetine | Avoid Use Five-fold increase in duloxetine exposure |
If unavoidable, monitor for duloxetine toxicity |
| Caffeine/Xanthine Derivatives | Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life | Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. |
|
|
||
| Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) | Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration |
Decrease ciprofloxacin absorption, resulting in lower serum and urine levels |
| Probenecid | Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) | Potentiation of ciprofloxacin toxicity may occur. |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
|
|
|
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|
|
| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| voriconazole | quinupristin/dalfopristin | colchicine | ||
| danazol | ||||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
|
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|
| Anticoagulants
|
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
|
| Antiplatelet Agents
|
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
|
| Nonsteroidal Anti-Inflammatory Agents
|
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
|
| Serotonin Reuptake Inhibitors
|
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone
|
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Lomitapide |
For patients with HoFH, do not exceed 20 mg simvastatin daily* |
| Grapefruit juice |
Avoid grapefruit juice |
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Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
|
Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (
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Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (
|
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|
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
|
|
During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (
|
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|
|
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
|
|
|
During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (
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The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
|
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|
During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
|
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
|
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|
During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
|
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib has no effect on methotrexate pharmacokinetics. |
|
|
During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
|
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|
Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
|
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|
During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
|
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|
|
Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (
|
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|
The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
|
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|
|
|
Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
|
|
|
During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
|
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|
|
Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
|
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|
Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (
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|
|
Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
|
|
|
Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (
|
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|
|
|
Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
|
Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
|
|
|
|
|
|
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
|
|
|
Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. |
|
|
|
|
|
NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
|
|
During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
|
|
|
|
|
Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
|
|
|
During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [
|
|
|
|
|
|
NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [
|
|
|
During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
|
|
|
|
|
|
Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
|
|
|
During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
|
|
|
|
|
|
Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
|
|
|
During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
|
|
|
|
|
|
Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
|
|
|
The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
|
|
|
|
|
|
Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
|
|
|
During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. |
|
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||||
|---|---|---|---|---|
|
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|
| Alpha Blockers |
|
tamsulosin |
|
|
| Analgesics |
methadone |
|
alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil |
|
| Antiarrhythmics |
disopyramide, dofetilide, dronedarone, quinidine |
|
digoxin |
|
| Antibacterials |
telithromycin, in subjects with severe renal impairment or severe hepatic impairment |
rifabutin |
telithromycin |
|
| Anticoagulants and Antiplatelet Drugs |
ticagrelor |
apixaban, rivaroxaban |
coumarins, cilostazol, dabigatran |
|
| Anticonvulsants |
|
carbamazepine |
|
|
| Antidiabetics |
|
|
repaglinide, saxagliptin |
|
| Antihelmintics and Antiprotozoals |
|
|
praziquantel |
|
| Antimigraine Drugs |
ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine) |
|
eletriptan |
|
| Antineoplastics |
irinotecan |
axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib |
bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids |
|
| Antipsychotics, Anxiolytics and Hypnotics |
lurasidone, oral midazolam, pimozide, triazolam |
|
alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone |
Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. |
| Antivirals |
|
simeprevir |
maraviroc, indinavir, ritonavir, saquinavir |
|
| Beta Blockers |
|
|
nadolol |
|
| Calcium Channel Blockers |
felodipine, nisoldipine |
|
other dihydropyridines, verapamil |
|
| Cardiovascular Drugs, Miscellaneous |
ranolazine |
aliskiren, sildenafil, for the treatment of pulmonary hypertension |
bosentan, riociguat |
|
| Diuretics |
eplerenone |
|
|
|
| Gastrointestinal Drugs |
cisapride |
|
aprepitant |
|
| Immunosuppres sants |
|
everolimus, temsirolimus |
budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus |
|
| Lipid Regulating Drugs |
lovastatin, simvastatin |
|
atorvastatin |
The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. |
| Respiratory Drugs |
|
salmeterol |
|
|
| Urological Drugs |
fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment |
darifenacin, vardenafil |
fesoterodine. oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine |
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| Other |
colchicine, in subjects with renal or hepatic impairment |
colchicine, conivaptan, tolvaptan |
cinacalcet |
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Norepinephrine Dopamine |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Reserve concomitant prescribing
of these drugs for use in patients for whom alternative treatment
options are inadequate. Limit dosages and durations to the minimum
required. Follow patients closely for signs of respiratory depression
and sedation |
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Benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. |
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The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. |
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If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue MS CONTIN if serotonin syndrome is suspected. |
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Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). |
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MAOI interactions with opioids
may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory
depression, coma) |
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Do not use MS CONTIN in patients taking MAOIs or within 14 days of stopping such treatment. |
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phenelzine, tranylcypromine, linezolid |
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May reduce the analgesic effect of MS CONTIN and/or precipitate withdrawal symptoms. |
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Avoid concomitant use. |
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butorphanol, nalbuphine, pentazocine, buprenorphine |
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Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of MS CONTIN and/or the muscle relaxant as necessary. |
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The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of MS CONTIN and/or cimetidine as necessary. |
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Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. |
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Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. |
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The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. |
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Monitor patients for signs of urinary retention or reduced gastric motility when MS CONTIN is used concomitantly with anticholinergic drugs. |
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The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death. |
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Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of MS CONTIN and/or the PGP-inhibitor as necessary. |
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Quinidine |
| *Change relative to reference |
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(Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Recommendation |
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Re-evaluate dosing. Do not exceed 8 mg/day |
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Re-evaluate dosing. Do not exceed 8 mg/day |
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Titrate dose upwards. Do not exceed twice the patient’s usual dose |
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| blood dyscrasias - see cancer collagen vascular disease congestive heart failure |
diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice |
hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency |
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| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Interacting Agents | Prescribing Recommendations |
| Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
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| nafcillin | carbamazepine | bosentan |
| rifampin | oxcarbazepine | octreotide |
| phenobarbital | orlistat | |
| phenytoin | sulfinpyrazone | |
| St. John's Wort | ||
| terbinafine | ||
| ticlopidine |
| ↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , )
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Avoid atorvastatin
|
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
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Do not exceed 20 mg atorvastatin daily
|
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)
|
Do not exceed 40 mg atorvastatin daily |
| *Not administered but an active metabolite of carbamazepine. | ||
| **No significant effect. | ||
| AED Coadministered |
AED Concentration |
Felbamate Concentration |
| Phenytoin | ↑ | ↓ |
| Valproate | ↑ | ↔** |
| Carbamazepine (CBZ) *CBZ epoxide |
↓ ↑ |
↓ |
| Phenobarbital | ↑ | ↓ |
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| * Antacids may affect absorption of phenytoin. † The induction potency of St. John's wort may vary widely based on preparation. |
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| Antiepileptic drugs |
Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate |
| Azoles |
Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole |
| Antineoplastic agents |
Capecitabine, fluorouracil |
| Antidepressants |
Fluoxetine, fluvoxamine, sertraline |
| Gastric acid reducing agents |
H2 antagonists (cimetidine), omeprazole |
| Sulfonamides |
Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim |
| Other |
Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin |
|
|
|
| Antacids* |
Calcium carbonate, aluminum hydroxide, magnesium hydroxide |
| Antineoplastic agents usually in combination |
Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate |
| Antiviral agents |
Fosamprenavir, nelfinavir, ritonavir |
| Antiepileptic drugs |
Carbamazepine, vigabatrin |
| Other |
Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John's wort†, sucralfate, theophylline |
|
|
|
| Antiepileptic drugs |
Phenobarbital, valproate sodium, valproic acid |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (> 1 quart daily) |
|
|
Concentration of Lamotrigine or Concomitant Drug |
|
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
|
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| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
|
|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
|
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|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
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|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓= Decreased (induces lamotrigine glucuronidation). | ||
| ↑= Increased (inhibits lamotrigine glucuronidation). | ||
| ? = Conflicting data. | ||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine concentrations approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine and carbamazepine epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? carbamazepine epoxide | May increase carbamazepine epoxide levels. | |
| Lopinavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir | ↓ lamotrigine | Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
| ? valproate | ||
|
|
|
| Anticoagulants
|
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
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| Antiplatelet Agents
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aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
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| Nonsteroidal Anti-Inflammatory Agents
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celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
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| Serotonin Reuptake Inhibitors
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citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone
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Norepinephrine Dopamine |
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| CYP2C9
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amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast
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aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
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| CYP1A2
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acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton
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montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
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| CYP3A4
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alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton
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armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide
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| Concomitant Drug Class: Drug Name | Effect on Concentration |
Clinical Comment |
|---|---|---|
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antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate) |
↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake) |
The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA. |
|
rifabutin |
↓ rilpivirine |
Concomitant use of COMPLERA with rifabutin may cause significant decreases in rilpivirine plasma concentrations (induction of CYP3A enzymes). If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of rifabutin coadministration. |
|
itraconazole ketoconazole posaconazole voriconazole |
↑ rilpivirine ↓ ketoconazole |
Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA. |
|
ledipasvir/sofosbuvir sofosbuvir/velpatasvir |
↑ tenofovir |
Patients receiving COMPLERA concomitantly with HARVONI® (ledipasvir/sofosbuvir) or EPCLUSA® (sofosbuvir/velpatasvir) should be monitored for adverse reactions associated with tenofovir DF. |
|
cimetidine famotidine nizatidine ranitidine |
↔ rilpivirine ↓ rilpivirine |
The combination of COMPLERA and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA. |
|
clarithromycin erythromycin telithromycin |
↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin |
Concomitant use of COMPLERA with clarithromycin, erythromycin, or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered. |
|
methadone |
↓ R(–) methadone ↓ S(+) methadone ↔ rilpivirine ↔ methadone |
No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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StrongCYP3A4Inhibitors (e.g.,itraconazole,clarithromycin) or strongCYP2D6inhibitors (e.g.,quinidine,fluoxetine,paroxetine) |
The concomitant use of aripiprazole tablets withstrong CYP3A4 orCYP2D6inhibitorsincreasedthe exposure ofaripiprazole tabletscomparedto the use of aripiprazole tabletsalone |
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inhibitororCYP2D6inhibitor, reducethearipiprazole tablets dosage |
| StrongCYP3A4Inducers (e.g.,carbamazepine,rifampin) |
The concomitant use of aripiprazole tabletsandcarbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone |
Withconcomitant use of aripiprazole tablets with a strongCYP3A4inducer, consider increasing the aripiprazole tabletsdosage |
| AntihypertensiveDrugs |
Duetoitsalphaadrenergicantagonism,aripiprazole tablets hasthepotentialtoenhance the effect of certainantihypertensive agents. |
Monitor bloodpressureand adjustdoseaccordingly |
| Benzodiazepines(e.g., lorazepam) |
Theintensityofsedationwas greaterwith the combination of oral aripiprazole tabletsandlorazepam as comparedtothat observedwith aripiprazole alone.Theorthostatichypotension observed wasgreaterwith the combination as comparedtothatobserved withlorazepamalone |
Monitorsedation and blood pressure.Adjust dose accordingly. |
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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Norepinephrine Dopamine |
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| ↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Lopinavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 50%. |
| Atazanavir/ritonavir |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 32%. |
| Phenobarbital/primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy. |
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| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
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| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – antagonist: maraviroc | ↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
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| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered:
No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole |
|
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| Endothelin receptor antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA. |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Long-acting beta-adrenoceptor agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses:
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Glucocorticoids Octreotide |
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Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
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Iodide (including iodine-containing Radiographic contrast agents) |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
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Hydantoins Phenobarbital Rifampin |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
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- Coumarin Derivatives - Indandione Derivatives |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
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- Interferon-α - Interleukin-2 |
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- Somatrem - Somatropin |
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- (e.g., Theophylline) |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
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Norepinephrine Dopamine |
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[CI: 17% decrease, 57% decrease] |
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[CI: 2% increase, 24% increase] |
[CI: 12% decrease, 51% decrease] |
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>1200-2400 |
up to 40% increase3 [CI: 12% increase, 60% increase] |
[CI: 3% decrease, 48% decrease] |
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[CI: 13% decrease, 40% decrease] |
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| Erythromycin (500 mg every 8 hrs) | +82% | +109% |
| Ketoconazole (400 mg once daily) | +135% | +164% |
| AED Co-administered | AED Concentration | Topiramate Concentration |
|---|---|---|
| NC = Less than 10% change in plasma concentration. NE = Not Evaluated |
||
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
| Concomitant Drug Class:
Drug Name |
Effect on
Concentration |
Clinical Comment |
|---|---|---|
| HIV Antiviral Agents: Reverse Transcriptase Inhibitors | ||
| Delavirdine | ↑ nelfinavir (C
min)
↓ delavirdine |
Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established. |
| Nevirapine | ↓ nelfinavir (C min) | Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established. |
| Didanosine | ↔ nelfinavir | There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food). |
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| Indinavir | ↑ nelfinavir
↑ indinavir |
Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. |
| Ritonavir | ↑ nelfinavir
↔ ritonavir |
Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established. |
| Saquinavir | ↑ nelfinavir
↑ saquinavir |
Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. |
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| Warfarin | Warfarin | Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy. |
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| Carbamazepine Phenobarbital
Phenytoin |
↓ nelfinavir ↓ phenytoin |
Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration. |
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| Trazodone | ↑ trazodone | Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered. |
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| Colchicine | ↑ colchicines | Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity.
Treatment of gout flares – co- administration of colchicine in patients on VIRACEPT: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
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| Rifabutin | ↑ rifabutin
↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID) |
It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin. |
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| Bosentan | ↑ bosentan | Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan:
Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability. |
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| Atorvastatin
Rosuvastatin |
↑ atorvastatin
↑ rosuvastatin |
Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day. |
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| Cyclosporine
Tacrolimus Sirolimus |
↑ immuno-suppressants
↑ nelfinavir |
Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir. |
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| Salmeterol | ↑ salmeterol | Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
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| Fluticasone | ↑ fluticasone | Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
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| Azithromycin | ↑ azithromycin | Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted. |
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| Methadone | ↓ methadone | Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT. |
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| Ethinyl estradiol
Norethindrone |
↓ ethinyl estradiol
↓ norethindrone |
Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered. |
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| Sildenafil
Vardenafil Tadalafil |
↑ PDE5 Inhibitors | Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution.
May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. • Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) • The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events. |
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| Omeprazole | ↓ nelfinavir | Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance. |
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| Quetiapine | ↑ quetiapine |
Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
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Avoid atorvastatin
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| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary | |
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Do not exceed 20 mg atorvastatin daily
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| HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily | |
| Classes of Drugs | ||
|---|---|---|
| Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics† |
Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics† |
Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins† |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 Induction) |
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(CYP450 inducer; P-gp inducer) |
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containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
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(CYP3A4 Inhibition) |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
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| Grapefruit juice | Avoid grapefruit juice |
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| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| Coadministered |
(mg/day) |
Dose (mg/day) |
Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400 to 2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 >1200 to 2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
| NA - Not available/reported | |||
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|||
| Digoxin Serum Concentration Increase |
Digoxin AUC Increase |
Recommendations | |
| Amiodarone | 70% | NA | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring. |
| Captopril | 58% | 39% | |
| Nitrendipine | 57% | 15% | |
| Propafenone | 35-85% | NA | |
| Quinidine | 100% | NA | |
| Ranolazine | 87% | 88% | |
| Ritonavir | NA | 86% | |
| Verapamil | 50-75% | NA | |
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|||
| Carvedilol | 16% | 14% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring. |
| Diltiazem | 20% | NA | |
| Nifedipine | 45% | NA | |
| Rabeprazole | 29% | 19% | |
| Telmisartan | 20% | NA | |
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| Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline | Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. | ||
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| Acarbose, Activated Charcoal, Albuterol, Antacids, Anticancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclpramide, Miglitol, Neomycin, Rifampin, Salbutamol, St.John's Wort, Sucralfate, Sulfasalazine | Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary. | ||
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| Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. | No additional actions are required. | ||
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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• Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
| |
Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents(e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptakeinhibitors (SNRIs) for signs of bleeding [ |
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|
| |
Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin doesnot produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitantuse of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactionsas compared to use of the NSAID alone [ |
| |
Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of theincreased risk of bleeding [ Celecoxib is not a substitute for low dose aspirin for cardiovascular protection. |
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| |
• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
| |
• During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect ofloop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to theNSAID inhibition of renal prostaglandin synthesis. |
| |
During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function,in addition to assuring diuretic efficacy including antihypertensive effects [ |
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The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration andprolong the half-life of digoxin. |
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During concomitant use of celecoxib and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance |
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During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g.,neutropenia, thrombocytopenia, renal dysfunction). |
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During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renalfunction. |
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Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk ofGI toxicity, with little or no increase in efficacy [ |
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The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associatedmyelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinineclearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives(e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five daysbefore, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhancethe exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin)may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosageadjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ |
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Evaluate each patient’s medical history when consideration is given to prescribing celecoxib. A dosageadjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ |
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Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [ |
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|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
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| Grapefruit juice | Avoid grapefruit juice |
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| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours | |
| Allopurinol | |
25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentratrions of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance in unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increase theophylline clearance. | 20% increase |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% increase |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects;possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. | Serum theophylline and phenytoin concentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% increase |
| Tacrine | Similar to cimetidine, also increases renal clearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
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| Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Lomitapide | For patients with HoFH, do not exceed 20 mg simvastatin daily
|
| Grapefruit juice | Avoid grapefruit juice |
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Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
|
|
Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [
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Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [
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Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [
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Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [
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The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. |
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During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels. |
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NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
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During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity. |
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Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Celecoxib capsules have no effect on methotrexate pharmacokinetics. |
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During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity. |
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Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. |
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During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function. |
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Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [
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The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended. |
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Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
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During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
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Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib. |
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [
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Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [
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Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding. |
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Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see
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| Antiarrhythmics:
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| Disopyramide
Quinidine Dofetilide Amiodarone Sotalol Procainamide |
Not Recommended |
Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. |
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| Digoxin | Use With Caution |
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| Oral Anticoagulants:
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| Warfarin | Use With Caution |
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| Antiepileptics:
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| Carbamazepine | Use With Caution |
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| Antifungals:
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| Itraconazole | Use With Caution |
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| Fluconazole | No Dose Adjustment
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| Anti-Gout Agents:
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| Colchicine (in patients with renal or hepatic impairment)
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Contraindicated |
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| Colchicine (in patients with normal renal and hepatic function) | Use With Caution | ||||
| Antipsychotics:
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| Pimozide | Contraindicated |
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| Quetiapine |
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| Antispasmodics:
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| Tolterodine (patients deficient in CYP2D6 activity) | Use With Caution |
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| Antivirals:
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| Atazanavir | Use With Caution |
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| Saquinavir (in patients with decreased renal function) |
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| Ritonavir
Etravirine |
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| Maraviroc |
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| Boceprevir (in patients with normal renal function)
Didanosine |
No Dose Adjustment |
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| Zidovudine |
The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated. |
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| Calcium Channel Blockers:
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| Verapamil | Use With Caution |
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| Amlodipine
Diltiazem |
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| Nifedipine |
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| Ergot Alkaloids:
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| Ergotamine
Dihydroergotamine |
Contraindicated |
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| Gastroprokinetic Agents:
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| Cisapride | Contraindicated |
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| HMG-CoA Reductase Inhibitors:
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| Lovastatin
Simvastatin |
Contraindicated |
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| Atorvastatin
Pravastatin |
Use With Caution | ||||
| Fluvastatin
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No Dose Adjustment
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| Hypoglycemic Agents:
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| Nateglinide
Pioglitazone Repaglinide Rosiglitazone |
Use With Caution |
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| Insulin |
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| Immunosuppressants:
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| Cyclosporine | Use With Caution |
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| Tacrolimus |
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| Phosphodiesterase inhibitors:
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| Sildenafil
Tadalafil Vardenafil |
Use With Caution |
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| Proton Pump Inhibitors:
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| Omeprazole | No Dose Adjustment |
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| Xanthine Derivatives:
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| Theophylline | Use With Caution |
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| Triazolobenzodiazepines and Other Related Benzodiazepines:
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| Midazolam | Use With Caution |
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| Alprazolam
Triazolam |
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. |
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| Temazepam
Nitrazepam Lorazepam |
No Dose Adjustment |
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| Cytochrome P450 Inducers:
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| Rifabutin | Use With Caution |
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| Other Drugs Metabolized by CYP3A:
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| Alfentanil
Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort |
Use With Caution | There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. | |||
| Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
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| Hexobarbital
Phenytoin Valproate |
Use With Caution | There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
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| Antifungals:
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| Itraconazole
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Use With Caution |
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| Antivirals:
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| Atazanavir | Use With Caution |
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to |
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| Ritonavir (in patients with decreased renal function) |
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. |
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| Saquinavir (in patients with decreased renal function) |
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| Etravirine |
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| Saquinavir (in patients with normal renal function) | No Dose Adjustment | ||||
| Ritonavir (in patients with normal renal function)
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| Proton Pump Inhibitors:
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| Omeprazole | Use With Caution |
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| Miscellaneous Cytochrome P450 Inducers:
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| Efavirenz
Nevirapine Rifampicin Rifabutin Rifapentine |
Use With Caution | Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see
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| Specific Drugs Reported | |||
| also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
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| alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone
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cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate
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6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone
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propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage
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| Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) |
The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage |
| Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) |
The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone |
With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage |
| Antihypertensive Drugs |
Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. |
Monitor blood pressure and adjust dose accordingly |
| Benzodiazepines (e.g., lorazepam) |
The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone |
Monitor sedation and blood pressure. Adjust dose accordingly. |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary digestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio
|
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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| Phenytoin |
NCor25%increasea
|
48%decrease |
| Carbamazepine(CBZ) |
NC |
40%decrease |
| CBZepoxideb
|
NC |
NE |
| Valproic acid |
11%decrease |
14%decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NCatTPM dosesupto400 mg/day |
13%decrease |
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose (5.12, |
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If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. |
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| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| |
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| |
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
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| Theophylline |
Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( |
| Warfarin |
Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( |
| Antidiabetic agents |
Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( |
| Phenytoin |
Monitor phenytoin level ( |
| Methotrexate |
Monitor for methotrexate toxicity ( |
| Cyclosporine |
May increase serum creatinine. Monitor serum creatinine ( |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin for oral suspension ( |